The postcardiac injury syndrome: case report and review of the literature.

Abstract: The postcardiac injury syndrome (PCIS) includes the postmyocardial infarction syndrome, the postcommissurotomy syndrome, and the postpericardiotomy syndrome. Dressler reported a series of patients who developed a pericarditis-like illness days to weeks after a myocardial infarction. Postcardiac injury syndrome also has been observed after cardiac surgery, percutaneous intervention, pacemaker implantation, and radiofrequency ablation.

Postcardiac injury syndrome is characterized by pleuritic chest pain, low-grade fever, an abnormal chest x-ray, and the presence of exudative pericardial and/or pleural effusions. The pathophysiology of PCIS involves auto-antibodies that target antigens exposed after damage to cardiac tissue.

The treatment of PCIS includes the use of nonsteroidal anti-inflammatory drugs and corticosteroids. Prophylactic use of corticosteroids before cardiac surgery has not been effective in preventing PCIS. The widespread use of reperfusion therapy and cardiac medications with anti-inflammatory properties may have reduced the incidence of PCIS. Although PCIS can follow a relapsing course, it does carry a favorable prognosis.

Key Words: postcardiac injury syndrome, postmyocardial infarction syndrome, postcommissurotomy syndrome, postpericardiotomy syndrome, Dressler syndrome.

Case Report

An 82-year-old Caucasian male with a history of hypertension, dyslipidemia, and cigarette smoking was referred to the Pulmonary Clinic for evaluation of a persistent, left-sided, exudative pleural effusion. The patient had been admitted to another hospital three times during the previous month. In the course of the first hospitalization, he was found to have new-onset atrial fibrillation, a pericardial effusion, and a left-sided pleural effusion. Diagnostic thoracentesis was consistent with an exudative effusion without evidence of infection or neoplasia. During the second hospitalization, he presented with fever, dyspnea, and pleuritic chest pain. He was diagnosed with a parapneumonic pleural effusion, started on antibiotics, and underwent therapeutic thoracentesis. During the third hospitalization, he presented with fatigue, weakness, and a persistent pleural effusion. The antibiotic coverage was broadened, therapeutic thoracentesis was repeated, and the patient was referred to the Pulmonary Clinic at our hospital.

Upon evaluation in the Pulmonary Clinic, the patient complained of malaise, fatigue, and dyspnea on exertion. He denied anginal or pleuritic chest pain. His past medical history was significant for hypertension, dyslipidemia, and glaucoma. His medications included Metoprolol, Ramipril, Hydrochlorothiazide, Levofloxacin, and Betaxolol eye drops. His social history was notable for infrequent alcohol consumption and a remote 15-pack per year history of cigarette smoking. His family, occupational, and travel histories were noncontributory.

The patient's vital signs were temperature 98.4[degrees]F, heart rate 82 beats per minute, blood pressure 136/47 mmHg, respiratory rate 17 breaths per minute, and pulse oximetry 94% on room air. His body mass index was 27 kg/[m.sup.2]. Upon examination, the patient was well-developed and well-nourished. He was alert, oriented, and in no acute distress. There was no palpable lymphadenopathy. There was dullness to percussion and diminished breath sounds over the left lower lung field. The remainder of the lungs were clear to auscultation. There was no jugular venous distention or hepatojugular reflux. The heart rate and rhythm were normal. The heart sounds also were normal without murmur, rub, or gallop. The peripheral pulses were easily palpable and symmetric. There was trace edema over the ankle and anterior tibia bilaterally.

Laboratory examination at our hospital was notable for an erythrocyte sedimentation rate (ESR) of 66 mm/h and a brain natriuretic peptide (BNP) of 600 pg/mL (Table 1). An electrocardiogram (EKG) revealed normal sinus rhythm with right bundle branch block and left anterior hemiblock. A chest x-ray (CXR) confirmed the presence of a moderate-sized, left-sided pleural effusion (Fig. 1). A transthoracic echocardiogram (TTE) revealed a left ventricular ejection fraction greater than 65% without focal wall motion abnormalities and a small pericardial effusion without tamponade physiology. Repeat thoracentesis was performed, and pleural fluid analysis was consistent with an exudative effusion, again without evidence of an infectious or neoplastic etiology (Table 2).

Given the constellation of fever, pleuritic chest pain, an elevated ESR, a pericardial effusion, and an exudative pleural effusion in an elderly man with multiple risk factors for coronary artery disease (CAD), the diagnosis postmyocardial infarction syndrome (PMIS) was favored. To further investigate the presence of CAD, the patient underwent an exercise sestamibi, which revealed a large, transmural, lateral-wall

perfusion defect. Cardiac catheterization revealed high-grade stenoses of the left anterior descending and left circumflex coronary arteries. Percutaneous intervention with deployment of Sirolumuseluting stents in both coronary arteries was performed successfully.

The patient was started on standard medical therapy for CAD, including Aspirin, Clopidogrel, Atenolol, Ramipril, and Simvastatin. For treatment of PMIS, he was started on Prednisone 40 mg daily, with a slow taper over the next month. During a four-week follow-up period, the patient's symptoms of dyspnea and pleuritic chest pain improved greatly, and the left-sided pleural effusion resolved fully (Fig. 2).

Historical Background

Postcardiac injury syndrome is an umbrella term that includes the PMIS, postcommissurotomy syndrome (PCS), and postpericardiotomy syndrome (PPS). William Dressler (1) first described PMIS in several reports published in the mid 1950s. His largest case series included 44 patients who developed a pericarditis-like illness days to weeks after myocardial infarction. Dressler described PMIS as an "annoying" complication that had a "benign" outcome. He suspected that PMIS was due to the release of auto-antigens that cause a "hypersensitivity reaction". Postmyocardial infarction syndrome often is referred to as Dressler syndrome (DS).

Janton et al (2) observed PCS in patients who had undergone surgery for treatment of rheumatic mitral stenosis. Ito et al (3) described PPS in patients who had undergone surgery for correction of congenital heart defects. Postcardiac injury syndrome (PCIS) also has been observed after traumatic hemopericardium, minimally invasive coronary artery bypass surgery, percutaneous transcoronary angioplasty, percutaneous intervention, pacemaker implantation, and percutaneous radiofrequency ablation. (4-9)

Pathophysiology of Postcardiac Injury Syndrome

Numerous mechanisms have been proposed for the development of PCIS. In the 1950s, Dressler attributed PMIS to a hypersensitivity reaction, whereas Janton attributed PCS to the reactivation of rheumatic fever, and Ito attributed PPS to traumatic pericarditis. In the 1970s, Burch and Colcolough (10) and Engle et al (11) hypothesized that PCIS was due to the reactivation of a latent viral infection, such as Coxsackie B.

Dressler anticipated the contemporary theory of the pathophysiology of PCIS, which proposes the induction of antiheart antibodies (AHA) against autoantigens that are exposed following cardiac injury. He wrote, "It may be that an antigen produced by myocardial necrosis leads, in susceptible persons, to the formation of autoantibodies which cause the postmyocardial-infarction syndrome, similar to the way in which surgical trauma may be the cause of the related postcommissurotomy syndrome." (1)

Elevated AHA titers among patients with PMIS, PCS, and PPS were documented in the early 1960s. (12,13) Antimyocardial antibodies have been detected in the pleural fluid of patients with PCIS. (14) McCabe et al (15) demonstrated a correlation between AHA titers and the incidence of PPS among 60 patients who had undergone cardiac surgery at Cornell Medical Center in the early 1970s. Among the 16 patients with high AHA titers, 14 (94%) developed PPS. Among the 31 patients with low AHA titers, only 1 (3%) developed PPS. Among the 13 patients without detectable AHA, none developed PPS.

Diagnosis of the Postcardiac Injury Syndrome

The clinical manifestations of PCIS are nonspecific. Seltzner et al (16) published a case series of 35 patients with PCIS seen at the University of Colorado Health Sciences Center between 1971 and 1981. The most common symptoms were pleuritic chest pain (91%) and dyspnea (57%). The most common signs were fever (66%) and pericardial friction rub (63%). The most common lab findings were an elevated ESR (96%) and leukocytosis (49%). The majority of patients (83%) had evidence of a pleural effusion on chest x-ray. The pleural effusion was exudative in all patients.

Postcardiac injury syndrome is a diagnosis of exclusion. Depending on the patient and his or her clinical presentation, the physician must consider acute coronary syndrome, heart failure, pulmonary embolism (PE), and pneumonia in the differential diagnosis. As always, the history and physical examination are vitally important. Initial evaluation should include a complete blood count, ESR, EKG, and CXR. Additional tests to consider include cardiac markers, BNP, arterial blood gas, TTE, and ventilation-perfusion scan or computed tomography scan with PE protocol. If thoracentesis is performed, pleural fluid analysis should include measurement of total protein, lactate dehydrogenase, cell count with differential, Gram stain, culture, and cytology. Antiheart antibodies are not routinely performed.

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Clinical Trials in the Postcardiac Injury Syndrome

Few randomized clinical trials have examined the management of PCIS. Horneffer et al (17) conducted a trial at The Johns Hopkins Hospital between 1984 and 1986 in which 149 adult patients with PCIS following cardiac surgery were randomized to receive either Ibuprofen 600 mg po four times per day, Indomethacin 25 mg po four times per day, or placebo for 10 days total. The rate of resolution of PCIS symptoms and signs after 10 days of treatment was 91% in the Ibuprofen group, 88% in the Indomethacin group, and 59% in the placebo group. The rate of termination of treatment due to side effects was 17% in the Ibuprofen group, 20% in the Indomethacin group, and 18% in the placebo group. The rate of relapse at 30 days was 25% in both the Ibuprofen and Indomethacin groups and 50% in the placebo group. Horneffer et al (17) concluded that nonsteroidal anti-inflammatory drugs (NSAIDs) effectively and safely relieve the symptoms and signs of PCIS while reducing the rate of relapse by half.

Mott et al (18) conducted a trial at Texas Children's Hospital between 1996 and 1998 in which 246 pediatric patients undergoing cardiac surgery were randomized to receive either Solumedrol or placebo. Those patients in the treatment group received Solumedrol (1 mg/kg IV for one dose preoperatively and 1 mg/kg IV every six hours for four doses postoperatively). The incidence of PPS was 17% in the treatment group and 15% in the placebo group. The rate of uncomplicated PPS was 62% in the treatment group and 94% in the placebo group. The rate of complicated PPS (defined as requiring readmission to the hospital, thoracentesis, or pericardiocentesis) was 38% in the treatment group and 6% in the placebo group. They concluded that prophylactic administration of Solumedrol does not prevent PPS while predisposing patients to complicated PPS.

Therapy of the Postcardiac Injury Syndrome

The treatment of PCIS includes the use of NSAIDs and corticosteroids. Nonsteroidal anti-inflammatory drugs must be prescribed at a sufficient dose, eg, Ibuprofen 2,400 mg daily divided TID or QID. Given its antiplatelet effects, aspirin may be the NSAID of choice for patients with PMIS.

Due to the multiple adverse effects of corticosteroids, Khan (19,20) has recommended limiting their use to those patients who are intolerant of or unresponsive to NSAIDs as well as to those who require narcotic analgesics. When used, corticosteroids must be prescribed at a moderately high dose and tapered gradually to prevent relapse of PCIS. A reasonable regimen would start with Prednisone 60 mg per day and reduce the daily dose by 5 mg per week. Therapeutic thoracentesis should be performed for large pleural effusions causing respiratory compromise. Pericardiocentesis should be performed for pericardial effusions causing life-threatening tamponade.

Prognosis of the Postcardiac Injury Syndrome

In general, the prognosis of PCIS is favorable. Welin et al (21) published a series of 1,809 patients in Goteborg, Sweden, who suffered myocardial infarction (MI) between 1968 and 1979. Only 60 (3%) of those patients developed PMIS within one year of their MI, 39 (65%) within the first three months and 21 (35%) within the next nine months. Most (60%) of the patients with PMIS were treated with corticosteroids, which resulted in prompt symptom relief but did not alter their morbidity or mortality as compared with the PMIS patients who did not receive corticosteroids. No major complications occurred among the patients with PMIS. The five-year mortality rate was higher among PMIS patients as compared with those MI patients without PMIS (26% v 18%), but this difference was not statistically significant.

The most feared complication of PCIS is graft occlusion in patients who develop PPS following coronary artery bypass graft (CABG) surgery. Urschel et al (22) published a series of 45 patients who developed PPS following CABG surgery at Baylor University Medical Center between 1968 and 1976. Among the first 14 patients, none of whom were treated with corticosteroids, the incidence of graft occlusion was 86%. Among the next 31 patients, all of whom were treated with aspirin plus Prednisone, the incidence of graft occlusion was only 16%. Urschel et al (22) concluded that treatment with NSAIDs and corticosteroids greatly reduces the risk of graft occlusion in patients with PPS status-post CABG surgery.

Postcardiac Injury Syndrome in the Reperfusion Era

Bendjelid and Pugin (23) recently proposed the question: "Is the Dressler Syndrome dead?" They noted that in Dressler's era, the reported incidence of PMIS was as high as 5% among patients with an acute myocardial infarction (MI). In the current era of reperfusion therapy utilizing either IV thrombolysis or percutaneous intervention, the occurrence of DS is exceedingly uncommon. In a series of 201 patients who underwent thrombolysis for acute MI, only one (0.5%) developed PMIS. This observation generated the hypothesis that reperfusion therapy limits myocardial infarct size and prevents the inflammatory or autoimmune process that leads to PMIS. (24)

According to Bendjelid and Pugin, (23) this is an incomplete explanation for the decreased incidence of DS. They hypothesize that the modern pharmacotherapy for MI also has contributed to the decreased incidence of PMIS. They cite evidence that three major classes of medications used to treat MI--angiotensin-converting enzyme inhibitors, beta blockers, and HMG-CoA reductase inhibitors--all have anti-inflammatory effects that may prevent PMIS. As these same classes of medications are used to treat patients who have undergone CABG surgery, they also might reduce the incidence of PPS. (23) Spodick (25) accepts these hypotheses but suggests that some cases of apparently idiopathic pericarditis in adults may represent PMIS following a silent MI.

Conclusion

In summary, PCIS includes PMIS, PCS, and PPS. The syndrome is characterized by pleuritic chest pain, elevated ESR, abnormal chest x-ray, and the presence of exudative pericardial and/or pleural effusions. The proposed pathophysiology of PCIS involves AHA that target auto-antigens exposed after damage to cardiac tissue. The treatment of PCIS includes the use of both NSAIDs and corticosteroids. Prophylactic use of corticosteroids before cardiac surgery has not been effective in preventing PCIS. The widespread use of reperfusion therapy and cardiac medications with anti-inflammatory properties may have reduced the incidence of PCIS. Although PCIS can follow a relapsing course, it does carry a favorable prognosis.

Acknowledgments

The authors would like to recognize Dr. Dennis Amundson for his critical review of the manuscript and Ms. Waine Macallister for her assistance in the preparation of this manuscript.

References

1. Dressler W. The postmyocardial infarction syndrome. Arch Int Med 1959;103:28-42.

2. Janton OH, Glover R, O'Neil TJ, et al. Results of the surgical treatment for mitral stenosis: analysis of 100 consecutive cases. Circulation 1952;6:321-333.

3. Ito T, Engle MA, Goldberg HP. Postpericardiotomy syndrome following surgery for nonrheumatic heart disease. Circulation 1958;17:549-556.

4. Tabatznik B, Isaacs JP. Postpericardiotomy syndrome following traumatic hemopericadium. Am J Cardiol 1961;7:83-96.

5. Burgwardt K, Smally AJ. Postpericardiotomy syndrome following minimally invasive coronary artery bypass. J Emerg Med 1998;16:737-739.

6. Velander M, Grip L, Mogensen L. The postcardiac injury syndrome following percutaneous transluminal coronary angioplasty. Clin Cardiol 1993;16:353-354.

7. Hearne C, Forjouh SN. Postcardiac injury syndrome after coronary angioplasty and stenting. J Am Board Fam Pract 2003;16:73-74.

8. Snow ME, Agatston AS, Kramer C, et al. The postcardiotomy syndrome following transvenous pacemaker insertion. Pacing Clin Electrophysiol 1987;10:934-936.

9. Turitto G, Abordo MG Jr, Mandawat MK, et al. Radiofrequency ablation for cardiac arrhythmias causing postcardiac injury syndrome. Am J Cardiol 1998;81:369-370.

10. Burch GE, Colcolough HL. Postcardiotomy and postinfarction syndromes: a theory. Am Heart J 1970;80:290-291.

11. Engle MA, Zabriskie JB, Senterfit LB, et al. Viral illness and the postpericardiotomy syndrome: a prospective study in children. Circulation 1980;62:1151-1158.

12. Robinson J, Brigden W. Immunological studies in the post-cardiotomy syndrome. Br Med J 1963;5359:706-709.

13. Van der Geld H. Anti-heart antibodies in the postpericardiotomy and the postmyocardial-infarction syndromes. Lancet 1964;18:617-621.

14. Kim S, Sahn SA. Postcardiac injury syndrome: An immunologic pleural fluid analysis. Chest 1996;109:570-572.

15. McCabe JC, Ebert PA, Engle MA, et al. Circulating heart-reactive antibodies in the postpericardiotomy syndrome. J Surg Res 1973;14:158-164.

16. Seltzner TJ, King TE Jr, Antony VB, et al. The pleuropulmonary manifestations of the postcardiac injury syndrome. Chest 1983;84:383-387.

17. Horneffer PJ, Miller RH, Pearson TA, et al. The effective treatment of postpericardiotomy syndrome after cardiac operations: a randomized placebo-controlled trial. J Thorac Cardiovasc Surg 1990;100:292-296.

18. Mott AR, Fraser CD Jr, Kusnoor AV, et al. The effect of short-term prophylactic methylprednisone on the incidence and severity of postpericardiotomy syndrome in children undergoing cardiac surgery with cardiopulmonary bypass. J Am Coll Cardiol 2001;37:1700-1706.

19. Khan AH. Pericarditis of myocardial infarction: review of the literature with case presentation. Am Heart J 1975;90:788-794.

20. Khan AH. The postcardiac injury syndromes. Clin Cardiol 1992;15:67-72.

21. Welin L, Vedin A, Wilhelmsson C. Characteristics, prevalence, and prognosis of postmyocardial infarction syndrome. Br Heart J 1983;50:140-145.

22. Urschel HC, Razzuk MA, Gardner M. Coronary artery bypass occlusion secondary to postcardiotomy syndrome. Ann Thorac Surg 1976;22:528-531.

23. Bendjelid K, Pugin J. Is Dressler syndrome dead? Chest 2004;126:1680-1682.

24. Sahar A, Hod H, Barabash GM, et al. Disappearance of a syndrome: Dressler's syndrome in the era of thrombolysis. Cardiology 1994;85:255-258.

25. Spodick DH. Decreased recognition of the post-myocardial infarction (Dressler) syndrome in the postinfarct setting: does it masquerade as 'idiopathic pericarditis' following silent infarcts? Chest 2004;126:1410-1411.

Dylan E. Wessman, MD and Christopher M. Stafford, MD

From the Department of Internal Medicine and the Division of Pulmonary and Critical Care Medicine, Naval Medical Center San Diego, San Diego, CA.

Reprint requests to Dr. Dylan E. Wessman, c/o Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134. Email: [e-mail]

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

Accepted October 24, 2005.

RELATED ARTICLE: Key Points

* The postcardiac injury syndrome includes the postmyocardial infarction syndrome, the postcommissurotomy syndrome, and the postpericardiotomy syndrome.

* Postcardiac injury syndrome is characterized by pleuritic chest pain, low-grade fever, an elevated erythrocyte sedimentation rate, an abnormal chest radiograph, and the presence of exudative pericardial and/or pleural effusions.

* The proposed pathophysiology of postcardiac injury syndrome involves auto-antibodies that target antigens exposed after damage to cardiac tissue.

* The treatment of postcardiac injury syndrome includes the use of both nonsteroidal anti-inflammatory drugs and corticosteroids.

* Although postcardiac injury syndrome can follow a relapsing course, it does carry a favorable prognosis.

Table 1. Laboratory data

Variable                           Result      Reference

Hemoglobin (g/dL)                       12.5        13.8-17.0
Hematocrit (%)                          37.3        40-50
White blood cell count (per          7,800       4,000-10,500
  [mm.sup.3])
Neutrophils (%)                         77.1        40-80
Lymphocytes (%)                         12.0        15-45
Monocytes (%)                            8.6         4-11
Eosinophils (%)                          2.2         0-6
Basophils (%)                            0.1         0-4
Platelet count (per [mm.sup.3])    378,000     150,000-450,00
Erythrocyte sedimentation rate          66           0-10
  (mm/hour)
Blood urea nitrogen (mg/dL)             18           8-26
Creatinine (mg/dL)                       1.1         0.7-1.2
Total protein (g/dL)                     5.5         6.1-7.9
Albumin (g/dL)                           2.5         3.5-4.8
Lactate dehydrogenase (IU/L)           125          99-192
Brain natriuretic peptide (pg/mL)      639           5-100
Thyroid stimulating hormone              2.68        0.35-5.50
  (MIU/mL)
Antinuclear antibody screen        Negative    Negative
Rheumatoid factor (IU/mL)              <20.0       <20.0
Coccidioides immitis serologies    Negative    Negative
Cryptococcus neoformans antigen    Negative    Negative

Table 2. Pleural fluid studies

Variable                        Result

Appearance                      Cloudy
Color                           Yellow
Red blood cell count (CU/mm)    3,680
White blood cell count (CU/mm)  2,080
Neutrophils (%)                    28
Lymphocytes (%)                     2
Monocytes (%)                       4
Eosinophils (%)                    30
Mesothelial cells (%)              36
Glucose (mg/dL)                   144
Total protein (g/dL)                3.8
Albumin (g/dL)                      2.0
Lactate dehydrogenase (IU/L)      151
Amylase (U/L)                      36
Triglyceride (mg/dL)               32
Gram stain                      No organisms seen
Bacterial culture               Negative
Fungal culture                  Negative
Acid-fast bacilli stain         No organisms seen
Acid-fast bacilli culture       Negative
Cytology                        No evidence of malignancy