# Pericardial Diseases
## Acute Pericarditis
### Etiology
The causes of acute pericarditis span a broad differential diagnosis. In developed countries, idiopathic and viral etiologies account for 80 to 90% of cases, with common viral agents including Coxsackievirus B, echovirus, adenovirus, Epstein-Barr virus, cytomegalovirus, HIV, and SARS-CoV-2. These cases are frequently preceded by an upper respiratory infection and tend to be self-limited. Autoimmune causes include systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren syndrome, vasculitis, sarcoidosis, and IgG4-related disease.
Post-myocardial infarction pericarditis occurs in two distinct clinical settings: early pericarditis developing within days of infarction as an inflammatory response to myocardial necrosis, and Dressler syndrome presenting 2 to 8 weeks post-infarction through an autoimmune mechanism. Post-cardiac surgery or post-procedural pericarditis, known as postpericardiotomy syndrome, affects 10 to 40% of patients undergoing cardiac surgery, and may also follow atrial fibrillation ablation procedures. Neoplastic pericarditis most commonly results from metastatic disease, with lung cancer, breast cancer, lymphoma, and melanoma being the most frequent primary tumors, while primary pericardial tumors such as mesothelioma are rare.
Uremic pericarditis occurs in advanced chronic kidney disease and end-stage renal disease, responds to dialysis, tends to be hemorrhagic, and does not respond to nonsteroidal anti-inflammatory drugs. Bacterial or purulent pericarditis, typically caused by Staphylococcus aureus, Streptococcus species, or gram-negative organisms, carries a high mortality rate and requires surgical drainage in addition to antibiotic therapy. Tuberculous pericarditis is common in endemic areas, presents with a subacute or chronic course, and carries a 30 to 50% risk of progression to constrictive pericarditis. Diagnosis relies on acid-fast bacilli smear and culture of pericardial fluid, adenosine deaminase levels exceeding 40 U/L, and interferon-gamma assays.
### Diagnostic Criteria (>= 2 of 4 Required)
The diagnosis of acute pericarditis requires the presence of at least two of four cardinal features. The characteristic chest pain is sharp and pleuritic, worsened by inspiration and the supine position, and improved by sitting forward. Radiation to the trapezius ridge is considered pathognomonic, as the phrenic nerve provides innervation to both the pericardium and the trapezius muscle. The pericardial friction rub is a scratchy, high-pitched sound best heard with the diaphragm of the stethoscope at the left sternal border with the patient leaning forward. It may have up to three components corresponding to atrial systole, ventricular systole, and early diastole, and is characteristically evanescent, often requiring serial auscultation.
Electrocardiographic changes follow a well-described four-stage evolution. Stage I, occurring in the acute phase over hours to days, demonstrates diffuse concave-upward ST elevation not confined to a single coronary territory, accompanied by PR depression most prominent in lead II with reciprocal PR elevation in aVR. Stage II shows normalization of ST segments. Stage III presents with diffuse T-wave inversions. Stage IV reflects complete normalization of all changes, though persistent T-wave inversions may occur in some patients. The fourth diagnostic criterion is new or worsening pericardial effusion on echocardiography.
### Additional Diagnostic Features
Inflammatory markers are elevated in the majority of cases, with C-reactive protein elevated in more than 75% of patients. C-reactive protein serves as the best marker for monitoring treatment response and guiding therapy taper. Troponin elevation occurs in 30 to 50% of cases, indicating concurrent myopericarditis, but does not change the prognosis when global left ventricular function is preserved. Focal subepicardial late gadolinium enhancement on cardiac magnetic resonance imaging is characteristic. Cardiac MRI provides definitive tissue characterization, demonstrating pericardial thickening and edema on T2-weighted sequences and late gadolinium enhancement of the pericardium indicating active inflammation. This modality is particularly valuable for differentiating pericarditis from myocardial infarction, which produces subendocardial or transmural late gadolinium enhancement in a coronary territory distribution.
### Pharmacotherapy for Pericarditis
| Agent | Dose | Duration | Key Trial Evidence | Notes |
|---|---|---|---|---|
| Aspirin | 750-1000 mg TID | 1-2 weeks, taper guided by CRP | -- | First-line NSAID (preferred post-MI) |
| Ibuprofen | 600 mg TID | 1-2 weeks, taper guided by CRP | -- | First-line NSAID alternative |
| Colchicine | 0.5 mg BID (0.5 mg daily if <70 kg) | 3 months (first episode); 6 months (recurrence) | COPE: recurrence 32% vs 11%; ICAP confirmed | Start at FIRST episode |
| Prednisone | 0.25-0.50 mg/kg/day | Slow taper over 3-6 months | -- | AVOID first-line; rapid taper causes recurrence |
| Anakinra (IL-1Ra) | 100 mg SC daily | Variable; taper after remission | AIRTRIP: 0% vs 67% recurrence | For corticosteroid-dependent recurrent pericarditis |
| Rilonacept (IL-1 trap) | Loading then weekly SC injection | Per protocol | RILP, RHAPSODY: significant recurrence reduction | FDA-approved for recurrent pericarditis |
| Azathioprine | 1-3 mg/kg/day | Steroid-sparing maintenance | -- | Second-line for refractory cases |
### Treatment
First-line therapy for acute pericarditis combines a nonsteroidal anti-inflammatory drug with colchicine. Aspirin at 750 to 1000 mg three times daily or ibuprofen at 600 mg three times daily is used, with taper over 1 to 2 weeks guided by C-reactive protein normalization. Colchicine at 0.5 mg twice daily, or 0.5 mg once daily for patients weighing less than 70 kg, is continued for 3 months. The COPE trial demonstrated that colchicine reduced pericarditis recurrence from 32% to 11%, a finding confirmed by the ICAP trial. Activity restriction is essential, with avoidance of strenuous exercise until symptoms resolve and C-reactive protein normalizes, with a minimum restriction period of 3 months for athletes.
Corticosteroids should be avoided as first-line therapy because they increase the risk of recurrence. They are reserved for cases with contraindications or failure of nonsteroidal anti-inflammatory drugs, autoimmune pericarditis, and uremic pericarditis. When used, low-dose prednisone at 0.25 to 0.50 mg/kg/day with a slow taper over 3 to 6 months is critical, as rapid taper is the most common cause of recurrent pericarditis. For refractory and recurrent cases, interleukin-1 targeted therapies have transformed management. The RILP trial demonstrated dramatic recurrence reduction with rilonacept, an interleukin-1 trap, while the AIRTRIP trial showed that anakinra, an interleukin-1 receptor antagonist, achieved a recurrence rate of 0% on therapy compared to 67% on placebo. Azathioprine serves as a steroid-sparing agent in selected cases.
### Recurrent Pericarditis
Recurrence occurs in 15 to 30% of patients after the first episode and in up to 50% without colchicine prophylaxis. Risk factors for recurrence include incomplete initial treatment, rapid corticosteroid tapering, and elevated C-reactive protein at the time of treatment discontinuation. Management of recurrence involves restarting the nonsteroidal anti-inflammatory drug plus colchicine combination, extending colchicine to 6 months, and adding anakinra or rilonacept as a steroid-sparing agent in corticosteroid-dependent cases. Rilonacept (Arcalyst) is FDA-approved for recurrent pericarditis and is administered as a weekly subcutaneous injection. The RHAPSODY trial demonstrated that rilonacept reduced recurrence and enabled successful corticosteroid tapering.
A four-stage ECG evolution diagram of acute pericarditis. Four horizontal ECG rhythm strips (lead II) stacked vertically with timeline labels. Stage I (acute, hours to days): diffuse concave-upward (smiley face) ST elevation with PR segment depression in lead II; PR elevation in aVR shown in small inset. Stage II (days to 1 week): ST segments normalize back to baseline; T waves remain upright. Stage III (1-3 weeks): diffuse T-wave inversions (symmetric, widespread) with isoelectric ST segments. Stage IV (weeks to months): normalization of T waves back to baseline (or persistent T-wave inversions in some patients). Each stage labeled with its name and typical timeline. Alongside the ECG, show a small cardiac diagram with the pericardial inflammation depicted (red inflamed pericardium in Stage I, progressively resolving through the stages). A key differentiating note from STEMI: "Pericarditis: diffuse ST elevation, PR depression, concave-up morphology, no reciprocal changes (except aVR). STEMI: territorial ST elevation, convex-up, reciprocal changes present."
## Pericardial Effusion
### Classification by Size
Pericardial effusions are classified by size on echocardiography. Small effusions demonstrate less than 10 mm of echo-free space in diastole and are typically confined to the posterior pericardial space. Moderate effusions measure 10 to 20 mm and are circumferential in distribution. Large effusions exceed 20 mm, are circumferential, and may demonstrate a swinging heart motion with electrical alternans on the electrocardiogram.
### Assessment for Tamponade Physiology
Echocardiographic evaluation for tamponade physiology is essential in any patient with a significant pericardial effusion. Right atrial systolic collapse lasting more than one-third of the cardiac cycle is the earliest and most sensitive echocardiographic sign, while right ventricular diastolic collapse is the most specific. Additional findings include inferior vena cava plethora with a diameter exceeding 2.1 cm and absent inspiratory collapse, exaggerated respirophasic variation in mitral inflow velocity with a decrease exceeding 25% in E-wave velocity during inspiration and tricuspid inflow increase exceeding 40%, and a swinging heart within the effusion. The clinical Beck triad of hypotension, muffled heart sounds, and elevated jugular venous pressure is classic but often presents incompletely. Pulsus paradoxus, defined as a systolic blood pressure decrease exceeding 10 mmHg with inspiration, is an important clinical finding, though its absence does not exclude tamponade, as it may be absent in the setting of atrial septal defect, severe aortic regurgitation, and loculated effusions with only regional compression.
### Pericardiocentesis
Indications for pericardiocentesis include cardiac tamponade, which constitutes an emergent indication, suspected bacterial or tuberculous pericarditis for diagnostic purposes, and large effusions for diagnostic workup in cases of suspected neoplastic or autoimmune etiology. The preferred technique is echo-guided percutaneous drainage using a subxiphoid approach with the Seldberg technique, with placement of a 6 to 8 French pigtail catheter left for drainage over 48 to 72 hours if significant effusion volume is present. Fluoroscopic guidance with aspiration of contrast to confirm intrapericardial position is used in the catheterization laboratory setting. Surgical drainage through pericardiectomy or pericardial window is reserved for recurrent effusions, loculated effusions, and cases of suspected purulent or malignant pericarditis requiring tissue biopsy.
### Pericardial Fluid Analysis
| Test | Finding | Suggests |
|---|---|---|
| Gross appearance | Serous | Viral, idiopathic, early TB |
| | Hemorrhagic | Malignancy, TB, uremia, trauma |
| | Purulent | Bacterial infection |
| Cell differential | Lymphocyte predominant | TB, malignancy, autoimmune |
| | Neutrophil predominant | Bacterial infection, early viral |
| Protein/LDH | Elevated (exudative) | Infection, malignancy, autoimmune |
| Glucose | Low | Bacterial, TB, rheumatoid |
| Cytology | Positive (~80% in malignant effusions) | Malignancy |
| ADA | >40 U/L (~90% sensitivity in endemic areas) | Tuberculosis |
| Cultures | AFB positive | Tuberculosis |
| PCR | Positive for TB or viral pathogens | Specific infectious etiology |
Analysis of pericardial fluid begins with assessment of gross appearance: serous fluid suggests viral, idiopathic, or early tuberculous etiology; hemorrhagic fluid points toward malignancy, tuberculosis, uremic disease, or trauma; and purulent fluid indicates bacterial infection. Cell count with differential reveals lymphocytic predominance in tuberculosis, malignancy, and autoimmune disease, while neutrophilic predominance suggests bacterial infection or early viral pericarditis. Protein and lactate dehydrogenase levels differentiate exudative from transudative effusions, analogous to Light criteria applied to pleural effusions. Low glucose levels are found in bacterial, tuberculous, and rheumatoid pericardial disease. Cytology is positive in approximately 80% of malignant effusions, with sensitivity increasing with repeated sampling. An adenosine deaminase level exceeding 40 U/L is suggestive of tuberculous pericarditis, with a sensitivity of approximately 90% in endemic areas. Additional analyses include tumor markers, polymerase chain reaction testing for tuberculosis and viral pathogens, and cultures.
## Constrictive Pericarditis
### Pathophysiology
Constrictive pericarditis results from a thickened, fibrotic, and/or calcified pericardium that restricts diastolic filling of the ventricles. Early diastolic filling remains normal, producing a rapid y descent, but filling abruptly ceases when cardiac volume reaches the limit imposed by pericardial constraint, creating the characteristic dip-and-plateau hemodynamic pattern. The hallmark pathophysiologic mechanism is enhanced ventricular interdependence: within the rigid pericardial shell, increased filling of one ventricle directly compromises filling of the contralateral ventricle. A related phenomenon is the dissociation of intrathoracic and intracardiac pressures. Inspiration normally decreases intrathoracic pressure, which is transmitted to the cardiac chambers to augment right-sided filling. In constriction, this negative intrathoracic pressure is not transmitted to the intracardiac space because of the rigid pericardium, reducing the transmural filling gradient and decreasing left ventricular filling during inspiration.
### Clinical Features
Clinical presentation is dominated by right heart failure symptoms, including peripheral edema, ascites that is often disproportionate to the degree of peripheral edema, hepatomegaly, and elevated jugular venous pressure. The Kussmaul sign, a paradoxical rise in jugular venous pressure with inspiration, is present in approximately 50% of patients. The pericardial knock is a high-pitched early diastolic sound heard at the lower left sternal border, corresponding to the abrupt cessation of ventricular filling at the point of pericardial constraint.
### Diagnosis
Echocardiography demonstrates several characteristic findings including a respirophasic septal bounce or shift, septal flattening, mitral E-velocity respiratory variation exceeding 25%, preserved or elevated medial e-prime velocity (annulus paradoxus), annulus reversus where medial e-prime exceeds lateral e-prime, and a dilated inferior vena cava. Computed tomography demonstrates pericardial thickening exceeding 4 mm and calcification, which is best detected on non-contrast imaging. It is important to note that calcification is present in only approximately 25% of surgically confirmed constriction cases. Cardiac magnetic resonance imaging demonstrates pericardial thickening on T1-weighted sequences and pericardial edema or inflammation on T2-weighted sequences and late gadolinium enhancement, with the latter findings suggesting a transient and potentially reversible form of constriction. Cardiac catheterization reveals equalization of diastolic pressures, the dip-and-plateau pattern, and discordant ventricular pressure changes with respiration, as detailed in the hemodynamics lecture.
### Treatment
Pericardiectomy is the definitive treatment for chronic constrictive pericarditis. Radical pericardiectomy with resection from phrenic nerve to phrenic nerve is preferred over partial pericardiectomy. Operative mortality ranges from 5 to 10%, with outcomes best when surgery is performed before NYHA Class IV symptoms develop, before severe hepatic dysfunction or renal failure ensues, and when the etiology is idiopathic or post-surgical. Radiation-induced constriction carries the worst surgical outcomes.
Before proceeding to pericardiectomy, a medical trial should be considered when an inflammatory component is suspected, as evidenced by pericardial edema or late gadolinium enhancement on cardiac MRI and elevated C-reactive protein. Anti-inflammatory therapy with nonsteroidal anti-inflammatory drugs plus colchicine or corticosteroids for 2 to 3 months may achieve resolution in approximately 20% of cases, representing transient constrictive pericarditis. Radiation-induced constriction carries the worst surgical prognosis, with mortality of 10 to 20%, often because of coexisting myocardial fibrosis and valvular disease that limit recovery after pericardiectomy. Tuberculous constriction requires anti-tuberculosis therapy for 6 months with early pericardiectomy if there is no response; the role of corticosteroids is controversial but may reduce the development of constriction, as suggested by a trend toward benefit in the IMPI trial.
A side-by-side comparison of cardiac tamponade versus constrictive pericarditis, showing key clinical, echocardiographic, and hemodynamic differences. Two columns with five rows. Row 1 (Clinical): Tamponade: acute presentation, hypotension, tachycardia, pulsus paradoxus, clear lung fields. Constriction: chronic presentation, elevated JVP with Kussmaul sign, peripheral edema with ascites, pericardial knock. Row 2 (Echo): Tamponade: RA systolic collapse, RV diastolic collapse, swinging heart, plethoric IVC. Constriction: septal bounce, respirophasic mitral inflow variation, preserved e' (annulus paradoxus), pericardial thickening. Row 3 (RA tracing): Tamponade: blunted y descent (impaired filling), prominent x descent. Constriction: prominent y descent (rapid early filling then halt), prominent x descent. Row 4 (JVP): Tamponade: elevated with inspiratory fall (normal). Constriction: elevated with Kussmaul sign (paradoxical inspiratory rise). Row 5 (Pericardium): Tamponade: large effusion (shown as blue fluid surrounding heart). Constriction: thickened/calcified pericardium (shown as thick white shell around heart, calcification spots marked). Each cell should contain a small illustration or waveform. Use red for tamponade column, blue for constriction column.
## Effusive-Constrictive Pericarditis
Effusive-constrictive pericarditis represents the coexistence of a significant pericardial effusion with constriction of the visceral pericardium. The hallmark of this entity is that after pericardiocentesis, filling pressures remain elevated because of persistent visceral pericardial constriction. The diagnosis is established when the post-drainage right atrial pressure remains greater than 50% of the pre-drainage value or persists above 10 mmHg. Common etiologies include tuberculosis, which is the most common cause worldwide, as well as idiopathic, post-radiation, post-surgical, and neoplastic causes. Treatment may include anti-inflammatory therapy, with pericardiectomy reserved for persistent constriction.
## Pericardial Tumors and Cysts
### Pericardial Cysts
Pericardial cysts are benign lesions that typically appear at the right cardiophrenic angle on chest radiography as smooth, thin-walled, fluid-filled structures on echocardiography, computed tomography, or cardiac magnetic resonance imaging. They are usually asymptomatic and discovered incidentally. Observation is the standard approach unless rare symptomatic compression of cardiac structures occurs.
### Pericardial Metastases
Pericardial metastases represent the most common pericardial malignancy, arising from metastatic spread of lung cancer, breast cancer, lymphoma, melanoma, and leukemia. These typically present with pericardial effusion that is often hemorrhagic, with tamponade a common clinical presentation. Management includes pericardiocentesis with cytologic analysis, pericardial window for recurrent effusions, systemic treatment of the underlying malignancy, and intrapericardial chemotherapy with agents such as cisplatin or thiotepa in selected cases.
### Primary Pericardial Mesothelioma
Primary pericardial mesothelioma is a rare malignancy associated with asbestos exposure that carries a poor prognosis with a median survival of less than 1 year. It may present with constrictive physiology or pericardial effusion. Diagnosis requires pericardial biopsy, and treatment options including debulking surgery, radiation, and chemotherapy have limited efficacy.
## Key Clinical Pearls
- Colchicine should be started with NSAIDs at the FIRST episode of pericarditis -- not only does it reduce recurrence by 50%, but it reduces the duration and severity of the acute episode
- Corticosteroids for pericarditis should be avoided if possible and used at LOW doses (0.25-0.50 mg/kg) with SLOW taper (over 3-6 months) -- rapid steroid taper is the most common cause of recurrent pericarditis
- Trapezius ridge pain radiation is pathognomonic for pericarditis (phrenic nerve C3-C5 innervates both the pericardium and the trapezius) and helps differentiate from myocardial ischemia
- In tamponade, do NOT assume the absence of pulsus paradoxus excludes the diagnosis -- pulsus paradoxus may be absent in ASD, significant aortic regurgitation, severe LV dysfunction, and loculated effusions with focal compression
- Constrictive pericarditis without pericardial calcification or thickening is possible -- up to 20% of surgically confirmed constriction has normal pericardial thickness; do not exclude constriction based solely on CT/MRI showing normal pericardial thickness
- IL-1 blockers (anakinra, rilonacept) have transformed the management of recurrent pericarditis -- patients with corticosteroid-dependent recurrent pericarditis should be referred to a pericardial disease specialist for biologic therapy consideration
## References
- Adler Y, et al. 2015 ESC Guidelines for the Diagnosis and Management of Pericardial Diseases. Eur Heart J. 2015;36:2921-2964.
- Imazio M, et al. Colchicine in Addition to Conventional Therapy for Acute Pericarditis (COPE). Circulation. 2005;112:2012-2016.
- Brucato A, et al. Rilonacept for Recurrent Pericarditis (RHAPSODY). NEJM. 2021;384:31-41.
- Imazio M, et al. Anakinra for Corticosteroid-Dependent and Recurrent Pericarditis (AIRTRIP). JAMA. 2016;316:1906-1912.
- Klein AL, et al. JACC Scientific Statement on Pericardial Diseases. JACC. 2023;82:1691-1756.