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The Pericardium and its Diseases
The Pericardium and its Diseases
The pericardium is a fibrous, relatively avascular tissue surrounding the heart which connects the heart to the sternum, diaphragm, and posteriorly to the anterior mediastinum. It consists of two layers: (1) the inner serous or visceral pericardium, also known as the epicardium; and (2) the outer fibrous parietal pericardium. The parietal pericardium consists of a fibrous sac that is less than 2 mm thick comprised mainly of collagen and some elastin fibers. Its fibrous nature and the relatively inelastic physical properties assist it to achieve its function of anchoring the heart in its position and preventing friction between the heart and the surrounding intrathoracic structures. In addition, the pericardium limits distention during the cardiac cycle and acts as an immunological barrier to infection. The inner visceral pericardium is comprised of a single layer of mesothelial cells attached to the epicardial surface of the heart muscle. To facilitate cardiac function and maintain effective function of the pericardium, the two layers of pericardium are separated by a potential space that contains 15–50 mL of serous fluid distributed mostly over the atrioventricular and interventricular grooves. The pericardium is a well-innervated structure such that pericardial inflammation can lead to severe pain and initiate vagally mediated reflexes. It also secretes prostaglandins that control cardiac reflexes and coronary tone. The incidence of pericarditis in postmortem studies ranges from 1–6%, whereas it is diagnosed antemortem only in about 0.1% of hospitalized patients and 5% of patients seen in emergency departments with chest pain but without myocardial infarction (MI). In other words, pericarditis constitutes up to 5% of the cases presenting to accident and emergency departments with non-ischemic chest pain and is therefore considered the most common form of pericardial disease. A prospective study published in 2008 reported the incidence of acute pericarditis was 27.7 cases per 100 000 of the population per year in an urban area of Italy.
Pericarditis is caused by a variety of etiological factors ( Table 16.1 ). The most common etiological factor is idiopathic pericarditis, which constitutes 80–90% of cases. The remaining 10% of cases have an infectious or non-infectious etiology. The most common infectious agent associated with pericarditis in the remaining 10% of cases is Mycobacterium tuberculosis. Other infectious agents include viruses such as echovirus, coxsackie virus, Epstein-Barr virus, cytomegalovirus, adenovirus and bacteria such as pneumococci, staphylococci, Haemophilus influenza, meningococci, gonococci, mycoplasma, Legionella and Chlamydia. Fungal and parasitic infections of the pericardium may occur, although they are rare.
TABLE 16.1
Classification of Pericarditis
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Among non-infectious causes, pericarditis usually follows a transmural MI. It can result from malignant cell invasion (neoplastic pericarditis); commonly due to metastasis from adjacent sites such as lung, breast, and lymphoma and rarely caused by primary pericardial tumors – mainly pericardial mesothelioma. Pericarditis may also develop due to the accumulation of blood in the pericardial space following a dissecting aortic aneurysm. It may also occur following sharp or blunt trauma to the chest as in penetrating thoracic injury or due to esophageal perforation. Iatrogenic causes of pericarditis are among the contemporary examples of post-cardiac injury syndromes and these occur following percutaneous coronary interventions, pacemaker insertion and catheter ablation. Chest radiation is another rare cause of pericarditis.
Autoimmune diseases predispose to the pericarditis. These include systemic lupus erythematosus (SLE), Sjögren syndrome, rheumatoid arthritis, systemic sclerosis, systemic vasculitides, Behçet syndrome, sarcoidosis, and familial Mediterranean fever. The most common metabolic causes of pericarditis include uremia and myxedema. Certain drugs are also among the rare causes of pericarditis. These can lead to the formation of pericarditis through differing mechanisms. Some of the drugs, such as procainamide, hydralazine, isoniazid (INAH), and phenytoin may cause SLE-like syndromes, which predispose to pericarditis, whereas doxorubicin and daunorubicin may predispose to cardiomyopathy and pericardiopathy. Penicillins cause hypersensitivity pericarditis with eosinophilia.
The clinical diagnosis of pericarditis is relatively easy to make, compared with the task of establishing its actual cause. The clinician needs to identify the specific causes of pericarditis that require targeted therapies. The most common presentation of pericarditis is chest pain, which is typically sudden in onset, retrosternal, pleuritic in nature and is exacerbated by inspiration. It is also exacerbated when the patient is in the supine position and relieved by sitting up or leaning forward. The pain often radiates to the neck, arms, or left shoulder. Typically, pericardial pain is referred to the scapular ridge, presumably due to irritation of the phrenic nerves, which passes adjacent to the pericardium. Therefore, if pain radiates to one or both trapezius muscle ridges, it is probably due to pericarditis, since the phrenic nerve (which also innervates these muscles) is irritated and passes adjacent to the pericardium. Chest pain can be severe and debilitating. However, pericarditis may at times be asymptomatic, as in pericarditis associated with rheumatoid arthritis. The pericardial friction rub is another classic finding of acute pericarditis. It is high-pitched and scratchy and can have up to three components. These components occur when the cardiac volumes are changing most rapidly during the different parts of the cardiac cycle. It corresponds temporally to the movement of the heart within the pericardial sac. Patients with atrial fibrillation have one or two components. A pleural friction rub can be differentiated from the pericardial friction rub by its absence when the patient holds his breath for a short time, whereas the pericardial friction rub continues even when the patient holds his/her breath.
The clinical diagnosis of pericarditis should be reserved for patients with an audible pericardial friction rub or chest pain with typical electrocardiographic findings, bearing in mind that the two most important conditions that may cause chest pain similar to that of pericarditis include myocardial infarction (MI) and pulmonary embolism. The clinical features that indicate a high-risk group of patients that need admission in order to search for the specific cause of pericarditis include fever (greater than 38°C), subacute course (symptoms develop over several days to weeks), large pericardial effusion (diastolic echo free space >20 mm in width), the development of cardiac tamponade and failure of aspirin therapy or NSAIDs.
Cardiac Tamponade
The presence of systemic arterial hypotension, tachycardia, elevated jugular venous pressure, and pulsus paradoxus (a decrease in systolic arterial pressure of more than 10 mmHg with inspiration) suggests cardiac tamponade. Cardiac tamponade is a potentially lethal complication of pericarditis. It is commonly reported in patients with tuberculous or purulent pericarditis (60%) and less commonly (15%) in patients with idiopathic pericarditis. The 12-lead electrocardiogram (ECG) in acute pericarditis typically shows diffuse concave ST-segment elevation and PR-segment depression. There are four stages of ECG abnormalities in pericarditis:
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Stage I: diffuse ST-segment elevation and PR-segment depression;
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Stage II: normalization of the ST and PR segments;
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Stage III: widespread T-wave inversions;
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Stage IV: normalization of the T waves.
There are several ECG changes that allow differentiation between MI and pericarditis. In MI, ST-segment elevations are usually convex (dome-shaped) and not concave as in pericarditis, and ST segment elevations are found in specific leads depending on the anatomical site of the MI. In contrast, the ST-segment changes are diffuse and widespread, affecting different leads in pericarditis. The ECG changes in pericarditis are less likely to be seen in certain leads such as aVR, and they are more likely seen in all other leads. In addition, PR-segment depression is more likely encountered in pericarditis and uncommon in MI. In contrast, Q-wave formation and loss of R-wave voltage is often seen in MI and not in pericarditis. Atrioventricular block or ventricular arrhythmias are commonly found in MI, and less likely to be found in association with the changes of pericarditis. In pericarditis, T-wave changes usually start after ST-segment elevations return to the base line (stage III), whereas in MI, it is common to find ST segments with concomitant T-wave inversions. In other words, T-wave inversions appear before the ST segments return to baseline. The most important and distinguishing feature is the ratio of ST-segment elevation (in millimeters) to T-wave amplitude (height in millimeters) in lead V6. If the ratio exceeds 0.24, acute pericarditis is almost always present. Chest imaging is usually performed to estimate the size of the heart and exclude abnormalities in the mediastinum, lungs or other organs surrounding the heart that might be responsible for the pericarditis. Cardiomegaly on chest imaging would suggest a significant pericardial effusion (more than 250 mL).
Serological Tests
Viral cultures and antibody titers are not useful clinically in diagnosing pericarditis. White cell count, erythrocyte sedimentation rate, and serum C-reactive protein concentration are generally elevated in patients with acute pericarditis, however, these tests are not useful for identifying the cause of the disease and do not provide clues regarding therapy. A marked increase in white-cell count indicates a purulent pericarditis; therefore, it is reasonable to obtain a complete blood count in all patients. Routine serologic testis, including testing for antinuclear antibody (ANA) and rheumatoid factor (RF), reveal a source for the pericarditis in only 10–15% of patients, and in these cases other evidence typically suggests the underlying disease. Plasma troponin concentrations are elevated in 35–50% of patients with pericarditis, a finding that is thought to be caused by epicardial inflammation rather than myocyte necrosis. The intensity of the elevation of serum troponin is related to the degree of ST-segment elevation. Serum troponin concentration usually returns to normal within two weeks after the diagnosis. An elevated troponin concentration does not predict an adverse outcome. A prolonged elevation (lasting longer than two weeks) suggests associated myocarditis, and this indicates a poor prognosis. Although the concentrations of serum creatine kinase and its MB fraction may also be elevated in pericarditis, they are abnormal less often than is the troponin concentration.
Echocardiography
Transthoracic echocardiography (TEE) is indicated in patients with suspected pericarditis, to confirm the diagnosis of pericarditis and to rule out cardiac tamponade, which necessitates pericardiocentesis.
Pericardiocentesis and Biopsy
Pericardiocentesis and pericardial biopsy are generally not useful in patients with small or moderate pericardial effusions, as a definitive diagnosis may not be provided. According to a study of 231 patients with acute pericarditis of unknown cause, pericardiocentesis provided the cause of pericarditis in 6% of cases and pericardial biopsy provided the diagnosis in 5% only. In contrast, in cases with pericardial tamponade, pericardiocentesis provided the diagnosis in 29% and pericardial biopsy provided a diagnosis in 54% of cases. Therefore, pericardiocentesis is often indicated in patients with pericardial tamponade and in patients with suspected purulent or neoplastic pericarditis. In pericardiocentesis, the pericardial fluid should be sent for analysis of red and white cell counts, cytology for cancer detection, and triglycerides to exclude a chylous effusion. Microscopic examination, in addition to culture and sensitivity of the pericardial fluid, is indicated to diagnose the specific microorganism that causes the pericardial effusion. Polymerase chain reaction (PCR) assays and adenosine deaminase activity levels (greater than 30 U per liter) are helpful in identifying Mycobacterium tuberculosis. Measuring the levels of glucose, lactic dehydrogenase, protein and pH is often a common practice in pericardiocentesis. However, testing for these levels does not provide the diagnosis for the specific cause of pericarditis.
Specific Forms of Pericarditis
Infectious Pericarditis
Idiopathic
Acute non-specific idiopathic pericarditis accounts for 80–85% of cases of acute pericarditis. It is seen in the fourth decade of life and shows a male predominance. Patients usually present with upper respiratory tract infection, congestive heart failure, pleural/pericardial effusion, leukocytosis, and raised erythrocyte sedimentation rate.
It has a self-limiting course. Rarely, patients may develop recurrence and constrictive pericarditis. Grossly, the pericardium initially looks shaggy and later develops fibrinous exudate and fibrous adhesions. Serous or serosanguineous pericardial effusion may be seen. Microscopically, the pericardium shows congestion and mixed inflammatory infiltrate.
Viral Pericarditis
Viral infections are responsible for 1–2% of cases of acute pericarditis. The most common causative viruses are coxsackievirus B, influenza, echovirus, and polio virus. Others include adenovirus, enterovirus, mumps virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis virus, herpes simplex virus (HSV), parainfluenza virus, varicella zoster virus (VZC), measles virus, and respiratory syncytial virus (RSV). Infections with the coxsackie virus and echovirus occur following the seasonal epidemic, while CMV infection is seen in the immunocompromised.
Viral pericarditis is usually associated with myocarditis and lasts for 1–3 weeks. It is self-limiting and has a good prognosis. Patients may present with sharp, stabbing chest pain, difficulty in breathing, dry cough, fever, fatigue, and swelling of ankles and feet. Occasionally, fibrous adhesions, constrictive pericarditis and recurrence can occur. Coxsackie viral pericarditis occurs following viral invasion of lungs and mesothelial cells and can cause post-infection dilated cardiomyopathy.
Viral pericarditis is diagnosed by examining the pericardial effusion using PCR or by in situ hybridization. A significant (four-fold) rise in serum antibody levels along with high interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and low transforming growth factor beta (TGFβ) in the pericardial fluid suggest the diagnosis of viral pericarditis.
AIDS-Associated Pericarditis
Pericardial involvement in AIDS occurs due to infectious, non-infectious and neoplastic diseases. Mild non-specific pericarditis is seen in approximately 50% of patients with AIDS while less than 1% of patients develop symptomatic pericarditis. Infective pericarditis can occur due to local HIV infection or due to opportunistic infections such as CMV, HSV, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare (MAI) and Cryptococcus. Small, asymptomatic pericardial effusion without cardiac tamponade is seen in 40% of cases.
Bacterial Pericarditis
Bacterial pericarditis, also called purulent pericarditis, is a less commonly encountered condition today compared to the pre-antibiotic era. It affects children more commonly than adults and usually occurs as a complication of infection affecting structures adjacent or contiguous to the pericardium. It may also occur due to infection that arises in distant organs and affects the pericardium by hematogenous spread. In adults, certain conditions such as pericardial effusion, immunosuppression, chronic illnesses, such as rheumatoid arthritis or alcohol abuse, cardiac surgery and chest trauma, can act as predisposing factors for purulent pericarditis. Purulent pericarditis can also be associated with other myocardial infections such as ring bacterial endocarditis and ring abscesses of native or prosthetic valves.
Gram-positive organisms including staphylococci, pneumococci, and streptococci are most commonly associated with purulent pericarditis. Staphylococcal pericarditis is now more likely to be found in patients infected with HIV, due to the high bacterial colonization of the nasal cavities and skin, and the high incidence of skin diseases in HIV-positive patients. In addition, it is related to the increased use of IV catheters in HIV-positive patients compared to those not HIV-positive. It is a life-threatening condition that can lead to cardiac tamponade. Pneumococcal pericarditis usually occurs as a result of direct extension of a lung or pleural infection, with only a few cases of primary pneumococcal pericarditis reported so far.
Infections with Gram-negative bacilli including Neisseria, E. coli, Haemophilus, Pseudomonas aeruginosa and Klebsiella pneumoniae are also among the common infectious organisms that predispose to purulent pericarditis. Primary infection of the pericardium is rare, and meningococcal pericarditis is frequently seen in epidemics. A study showed that meningococcal pericarditis was found in around 20% of patients with meningococcal meningitis. Meningococcal pericarditis is more common in children than adults and accounts for 33% and 2–4% of cases, respectively. Haemophilus influenza pericarditis is more commonly encountered in children than in adults.
Other infectious agents that lead to purulent pericarditis include Legionella pneumophila, Campylobacter, Listeria monocytogenes, Neisseria mucosae, Nocardia asteroids, and Chlamydia. Although anaerobic organisms are occasionally associated with purulent pericarditis, the most frequent anaerobic organisms associated with purulent pericarditis include Bacteroides fragilis and Clostridia species.
Grossly, both parietal and visceral pericardial layers appear to be thickened and may be covered by a fibrinopurulent exudate. The pericardial space may contain serous, serosanguineous, or turbid, yellow, green fluid. Microscopically, abundant infiltration of polymorphs is usually seen in the epicardium and the collected pericardial fluid.
The course of purulent pericarditis is usually acute, fulminant and requires immediate pericardiocentesis. The pericardial fluid should be sent for Gram staining, acid-fast and fungal stains, in addition to culture and sensitivity of the pericardial and other body fluids. Microorganisms can be demonstrated by Gram staining of the pericardial fluid before initiating antimicrobial treatment. Rinsing of the pericardial cavity, frequent drainage, in addition to systemic antibiotic therapy are all mandatory for effective treatment of purulent pericarditis. Surgery is indicated in patients with purulent pericarditis who develop complications such as dense fibrous adhesions, loculated and thick purulent effusion, tamponade, persistent infection, areas of calcification and progression to constrictive pericarditis. Purulent pericarditis is always fatal if left untreated. However, even in medically treated patients the mortality rate may reach up to 77%, with the main causes of death being cardiac tamponade, toxicity, and constriction.
Lyme Pericarditis
Lyme disease is caused by a spirochete (Borrelia burgdorferi), which is transferred by tick bite (Ixodes dammini). As Lyme disease develops, it progresses into three stages: local disease, early dissemination, and late dissemination. Cardiac involvement is seen in the second stage of the disease (the early dissemination stage) and the patient may present with arrhythmia, heart block, myopericarditis, and pancarditis. Microscopically mild interstitial fibrosis, lymphocytic infiltrate, myocarditis, pericarditis and conduction system abnormalities can be seen.
Tuberculous Pericarditis
Mycobacterium tuberculosis (TB) is a common cause of pericarditis worldwide. The prevalence of tuberculous pericarditis (TB pericarditis) has declined significantly in developed countries during the past four decades. During the last decade, it has been seen mainly in immunocompromised patients. Other forms of mycobacteria have also been reported in association with pericarditis such as Mycobacterium chelonae, and Mycobacterium avium intracellulare, which is mainly reported in HIV-positive patients. TB pericarditis occurs in less than 10% of patients affected by systemic tuberculosis. It is usually caused by spread of infection from the mediastinal, paratracheal, peribronchial lymph nodes or by hematogenous spread from other distant sites. It can also occur due to direct spread from a lesion affecting the lungs, sternum, or spine.
Tuberculous pericarditis is characterized by three stages: (1) acute; (2) subacute; and (3) chronic. The acute stage can be further subdivided into the fibrinous and effusive stages. In the fibrinous stage, patients may develop a serosanguineous effusion and lymphocytic infiltrate; while in the effusive stage, lymphocytes can be seen in the pericardial fluid. The subacute stage is characterized by the presence of granulomatous inflammation with or without caseous necrosis. The Mycobacterium can usually be detected in this stage using special stains. The chronic stage is characterized by the presence of marked pericardial thickening and fibrosis, calcification, obliteration of pericardial cavity and constrictive pericarditis.
The clinical presentation of TB pericarditis is variable. Patients may either present during the early stage of the disease (the effusive stage) or later after the development of constrictive pericarditis. During the effusive stage, patients may develop persistent fever, night sweats, dyspnea, abdominal discomfort, and jugular venous distention. Chest pain is less likely to be encountered in TB pericarditis and it usually indicates a viral etiology.
When pericarditis develops in patients with systemic tuberculosis, it is strongly suggestive that the causative microorganism is Mycobacterium tuberculosis. Sputum cultures and tuberculin skin tests can be done. The tuberculin skin test has less sensitivity and specificity with 25–33% false-negative and 30–40% false-positive cases. The enzyme-linked immunosorbent spot (ELISPOT) test is more accurate, it detects T-cells specific for Mycobacterium tuberculosis antigen. The diagnosis is usually established by demonstrating the presence of a serosanguineous effusion, lymphocytes and rarely the microorganism in the pericardial fluid or tissue in the early effusive stage of the disease, and/or by demonstrating the presence of caseating granulomas, with or without necrosis and microorganisms (with special stains) in the tissue biopsy in the subacute stage of the disease ( Figure 16.1 A,B). The diagnostic yield of pericardiocentesis in TB pericarditis ranges from 30–76%. The pericardial fluid in TB pericarditis usually demonstrates high specific gravity, high protein levels, and high white-cell count (from 0.7–54 × 10 9 /L). High adenosine deaminase activity and interferon gamma concentration in the pericardial fluid are diagnostic of TB pericarditis, with a high sensitivity and specificity. Pericardial biopsy allows diagnosis with a better sensitivity than pericardiocentesis (100% versus 33%). Other important diagnostic techniques include polymerase chain reaction (PCR), which can detect DNA of the Mycobacterium from only 1 μL of pericardial fluid in a very short time. In addition, both pericardioscopy and pericardial biopsy have improved the diagnostic accuracy for TB pericarditis.
Various antituberculous drug combinations of varying durations, ranging from 6–12 months, have been indicated. The use of steroids in treatment of TB pericarditis remains controversial. It has been suggested that antituberculous drug treatment combined with steroids might be associated with an infrequent need for pericardiocentesis or pericardiectomy, more rapid clinical improvement and reduced mortality. The prognosis of untreated effusive TB pericarditis is poor; constrictive pericarditis occurs in almost all patients and the mortality rate reaches up to 85%.
Fungal Pericarditis
Primary fungal infection of the pericardium is rare. The common fungal infectious agents that cause pericarditis include histoplasmosis, cryptococcosis, blastomycosis, and Candida species and rarely actinomycosis, cryptococcosis, and coccidioidomycoses. Fungal pericarditis usually occurs due to spread of infection from the adjacent structures such as lungs and pleural cavities. It can occur in patients with advanced malignancies or immunosuppressed state and caused by opportunistic infections including Candida, Aspergillus, and Blastomyces. It can also be seen in people living in areas with endemic fungal infections such as histoplasmosis.
Histoplasmosis
Fungal pericarditis due to Histoplasma capsulatum is rare, although it is commonly seen in endemic areas. Grossly, it can lead to fibrinous exudate with or without serosanguineous effusion. Microscopically, mixed inflammatory cell infiltrate composed of polymorphonuclear leucocytes and lymphocytes is seen. Sometimes granulomata associated with cell necrosis may also be seen. Areas of organization, focal calcification, and fibrosis may develop, which can lead to constrictive pericarditis. The diagnosis of histoplasmosis is made by the demonstration of fungus in the pericardial fluid and/or the biopsy using special stains and culture techniques. Other tests that may assist in diagnosing histoplasmosis include the demonstration of antifungal antibodies in the serum, histoplasma skin tests, and histoplasma complement fixation tests. Patients with pericarditis due to histoplasmosis do not need antifungal therapy, and they usually respond to non-steroidal anti-inflammatory drugs given during 2–12 weeks.
Candida
Candida pericarditis usually occurs in immunocompromised patients, especially those with deficient T-cell function. It can also occur in Candida endocarditis, especially following prosthetic valve surgery. The treatment involves the use of antifungal drugs such as fluconazole, ketoconazole, itraconazole, amphotericin B, liposomal amphotericin B, or amphotericin B lipid complex. Some studies have recommended that the combined use of medical therapy (Amphotericin B) along with surgery (pericardiectomy) is helpful for treatment. In general, pericardiocentesis is usually indicated in hemodynamic impairment while pericardiectomy is indicated in constrictive pericarditis. Purulent pericarditis due to Candida infection has a poor prognosis.
Parasitic Pericarditis
Pericardial involvement is rarely seen in parasitic infections.
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