Constrictive Pericarditis as a Post-Cardiac Surgery Complication
Constrictive pericarditis is a chronic inflammatory process characterized by chronic fibrosis, pericardial calcification, and impaired ventricular filling . Effusive-constrictive pericarditis (ECP) is a variant characterized by a constricting visceral pericardium and a pericardial effusion that can create a tamponade effect on the heart. It accounts for 2.4% to 14.8% of cases of constrictive pericarditis, and symptoms are similar to heart failure and volume overload. ECP has all of the features of constrictive pericarditis combined with a persistently high mean right atrial pressure >10 mmHg . The etiology is frequently unknown but can be similar to constrictive pericardial disease, including infection , medications , radiation , cardiac surgery , autoimmune disease , and malignancy . An initial attempt at conservative medical therapy may be successful if an underlying etiology can be discovered and treated, but in most cases the treatment is surgical . The diagnosis of ECP can be challenging because of often vague clinical presentations and broad differential diagnoses such as cardiac tamponade, restrictive cardiomyopathy, and right ventricular failure . This report describes a 62-year-old woman with a history of multiple myeloma, bone marrow transplantation, and treatment, with a remote history of exposure to chemotherapy who developed infective bacterial pericarditis and ECP with cardiac tamponade. It case shows the challenges of diagnosis and medical management of ECP.   A 62-year-old woman with a past medical history of multiple myeloma, 3 years status post autologous bone marrow transplantation (BMTx), and 2.5 years status post-treatment with daratumab, lenalidomide, bortezomib, and dexamethasone as chemotherapy, without evidence of relapse, was admitted to a hospital in Germany on October 2023 due to a pericardial effusion complicated by cardiac tamponade. Because of the posterior location of the pericardial effusion, a pericardiocentesis was considered too risky and would have compromised visualization. Consequently, the cardiac team performed an emergency sternotomy and pericardial washout. The pericardial fluid grew Haemophilus influenzae and Pseudomonas aeruginosa , and she received a long course of antibiotics. After a prolonged and complicated hospital course, she flew back to Orlando and presented to our hospital on her day of arrival because of progressive shortness of breath. The time that elapsed between the sternotomy and her presentation for shortness of breath was 3 months. In the Emergency Department (ED), she was in mild distress, hypotensive, and tachycardic. A physical examination revealed an elevated jugular vein distention (JVD) of 9 cm, minimally decreased breath sound in both bases, and bilateral pitting leg swelling. Her initial lab tests revealed low platelets of 25 000 (150 000 to 450 000/µL of blood), elevated alkaline phosphatase (ALP) of 260 IU/L (44 to 147 (IU/L), and B-type natriuretic peptide (BNP) of 1866 pg/mL (<100 pg/mL). Her electrocardiogram (ECG) showed nonspecific ST-T changes. A chest X-ray (CXR) showed a bilateral pleural effusion, more prominent on the right side. A transthoracic echocardiogram (TTE) showed a normal ejection fraction of 60–64%, along with a noticeable pericardial effusion and septal bounce sign . In addition, echocardiography showed an elevated mitral annular reverse velocity of 13.3 cm/s (normal is the forward velocity at the mitral annulus). Her e’/e’ was 7.7 (<14), medial e’ (tissue Doppler velocity at the medial mitral annulus)/lateral e’ (tissue Doppler velocity at the lateral mitral annulus) of 6.2 cm/s (<8 cm/s), suggesting constrictive pericarditis. Her right atrial (RA) pressures were 30/27, systolic and diastolic (mmHg), respectively, with a mean of 25 (1–7 mmHg). A computed tomographic angiogram (CTA) of the chest showed moderate pericardial effusion with hyperattenuating contents suggestive of hemopericardium along with mass effect on the right ventricle and reflux of contrast into the inferior vena cava (IVC) and hepatic veins, suggesting right heart dysfunction concerning for cardiac tamponade. The Cardiology Department was consulted, and the patient was admitted to the Coronary Care Unit (CCU) for suspected cardiac tamponade. Subsequently, right and left heart catheterizations were performed, and normal coronaries were observed. The hemodynamic tracing was generated by the simultaneous catheterization of the right (RV) and left (LV) ventricles and recording the pressure waveforms. It showed the respiratory discordance of systolic RV-LV pressures, which, along with the equalization of end-diastolic RV-LV pressures, was diagnostic of constrictive pericarditis. Because of the persistently elevated RA pressures and the effusion, she was diagnosed with ECP. An extensive infectious and autoimmune workup was negative. The cardiothoracic surgeons recommended against surgical intervention due to the presence of extensive postoperative adhesions and advised to continue medical treatment for 3 months before reevaluation. According to the cardiothoracic surgeon, pericardiectomy would be an option if medical therapy was deemed to be ineffective. In addition, the patient was not fit to undergo surgery due to symptomatic right heart failure. Colchicine, along with heart failure core measures and medications, was started and resulted in symptomatic improvement. The patient’s medications were torsemide 20 mg po daily, rosuvastatin 5 mg daily po, carvedilol 3.125 mg bid po, colchicine 0.6 mg bid (at time of dx of ECP), and lisinopril 5 mg po daily. We saw the patient in the outpatient clinic after 3 months of starting colchicine, and she reported modest improvement in her symptoms, with increased ability to perform her activities of daily living, with less shortness of breath.   The etiology of this case is unusual, and despite a second attack of cardiac tamponade and ECP, the patient responded favorably to conservative medical management. This is a case of an unexpected infectious pericardial effusion occurring 3 years after a bone marrow transplantation for light-chain Kappa with complex cytogenetics multiple myeloma. The patient’s chemotherapy included daratumab, lenalidomide, bortezomib, and dexamethasone, of which bortezomib and lenalidomide have been implicated in pericardial and myocardial adverse effects . The first pericardial effusion in Germany was antecedent to cardiac tamponade, which was treated with a sternotomy, pericardiectomy, and washout. Three months later, she presented with unresolved dyspnea, and her workup revealed ECP. There were contraindications for repeat cardiac surgery, and she was successfully treated with colchicine. There are previous reports of malignancies and chemotherapy causing ECP , including multiple myeloma. Multiple myeloma alone is rarely associated with pericardial involvement and cardiac tamponade without underlying pathology. Amyloidosis, infections, or plasma cell infiltration in patients with multiple myeloma have been reported to cause cardiac tamponade. However, Santana et al described a 53-year-old who was 3 years post-chemotherapy treatment for multiple myeloma and was admitted with dyspnea. His workup revealed constrictive pericarditis and metastatic multiple myeloma involving the pericardium . Our patient did not have recurrent malignancy involving the heart, but she had been taking potentially cardiotoxic chemotherapeutic agents. Both bortezomib and lenalidomide  are implicated as cardiotoxic drugs, but our patient was untreated with these agents for 30 months before her first cardiac tamponade, so it is highly unlikely chemotherapeutic drugs were the cause of the acute pericardial disease. Another case of medication-induced ECP was published in 1999. Woods et al  reported the case of a 47-year-old man with acute myelogenous leukemia with 1 month of fatigue and bleeding mucus membranes who developed transient ECP while taking cytarabine and daunorubicin. He recovered when the chemotherapeutic agents were discontinued. Pericardial space infection  is also a known risk for cardiac tamponade and ECP. Our patient’s first pericardial fluid culture was positive in Germany, and she received prolonged treatment. However, an extensive infectious workup when she was admitted to our hospital was negative. In addition, she improved in our center on colchicine without antibiotics, suggesting she was infection-free by the time she arrived at our hospital 3 months after her first event. Theoretically, the cardiac surgery and the pericardial infection with Hemophilus influenzae and Pseudomonas aeruginosa that occurred 3 months prior to admission to our hospital could have resulted in pericardial scarring, scar retraction, and debris deposition that promoted ongoing continued sterile inflammation. In this sense, the etiology of the ECP could be considered infectious but sterile. Viruses, tuberculosis, and even exotic bacteria are established etiologies of ECP . Rafailidis et al  even described the case of a 40-year-old patient with a 6-month history of dyspnea who was found to have effusive-constrictive calcific pericarditis associated with Streptococcus salivarius . Two patients with severe radiation pericarditis have been reported, but our patient never received radiation for her malignancy . Cardiac surgery is a known risk factor for ECP. In 2001, Ito et al  reported a 60-year-old woman who had undergone repair of an atrial septal defect and developed ECP 31 months after her procedure. Our patient’s ECP occurred 3 months after a pericardiectomy. In summary, it appears our patient’s ECP was a result of the pericardial damage from both the bacterial infection and the open surgery. The fact that the initial event occurred in her 7 th decade of life while she was abroad was also a complicating element. A high index of suspicion is required to recognize ECP, since no single diagnostic test provides a certain diagnosis. ECP is characterized by inadequate diastolic filling secondary to increased intrapericardial pressure, resulting in external chamber compression and loss of the elasticity of the epicardium. Clinically, up to 50% of patients will have a prodrome of fever and chest pain that will develop within 3 months of presentation . All patients will have evidence of predominant right-sided heart failure (HF) with JVD , as seen in our patient. TTE is usually the first diagnostic tool used to evaluate heart failure and requires a complete echocardiographic assessment with cross-sectional imaging. ECP presents with the presence of a fluid collection around the heart because of the involvement of the visceral pericardium . In addition, an elevated RA pressure and septal bounce can assist when diagnosing constrictive pericardial disease . Cardiac magnetic resonance imaging (cMRI) can also be a helpful imaging technique to demonstrate reduced pericardial motion, the septal bounce, and pericardial thickening that is characteristic of ECP, but was not necessary in our patient . Since the clinical features of ECP frequently overlap with cardiac tamponade, more invasive tests are occasionally utilized to differentiate between the 2 conditions . Cardiac catheterization has been the criterion standard for diagnosing ECP . In general, it has been reserved for selected cases or for assessment of concomitant coronary disease after a complete echocardiographic assessment with cross-sectional imaging . The fundamental pathological concepts of the diagnosis using invasive monitoring include evidence of enhanced ventricular interaction and a dissociation of intrathoracic and intra-cardiac pressures. In both ECP and cardiac tamponade, there is equalization of the right atrial (RA), right ventricular (RV), left ventricular (LV), and pulmonary wedge pressure. However, in cardiac tamponade, the pressure decreases with inspiration, whereas in ECP, the RA pressure remains constantly high at >10 mmHg, while the pulmonary wedge pressure decreases . In ECP, during diastole, the pressures of all 4 cardiac chambers increase enough to equalize with the pressure exerted by the thickened pericardium. The stiff, non-elastic pericardium prevents the transmission of intrathoracic pressure to the cardiac chambers, so there is a dissociation between intracardiac and intrathoracic pressures, resulting in a respiratory discordance of systolic RV-LV pressures. Both LV and RV are constricted within this shell so that a change in volume of one chamber reflects upon the other, which is called ventricular interdependence, which was present in this patient. In normal hearts, the diastolic pressures in the ventricles vary independently and remain unaffected by the other ventricles. In ECP the ventricular interdependence leads to decreased venous return with inspiration as pulmonary venous pressure decreases . Also, in ECP, during the early diastole, the ventricular filling is not affected and is only impeded when the elastic limit of the pericardium is reached, in contrast to cardiac tamponade, in which the ventricular filling is impeded throughout diastole, leading to a decreased end-diastolic volume and impaired cardiac output . Differentiation of ECP from restrictive cardiomyopathy can be challenging as some patients with ECP have a history of definite or possible acute pericarditis. Factors such as previous cardiac surgery, radiotherapy, connective tissue disease, and thoracic trauma may be the background for development of ECP, and none of these factors are expected in the medical history of patients with restrictive cardiomyopathy. Cardiac catheterization studies have perhaps received too much emphasis to differentiate between ECP and restrictive cardiomyopathy. A carefully conducted hemodynamic study is likely to yield important clues. The treatment of ECP depends on the hemodynamic stability of the patient and the etiology of the pericardial damage. Cardiac tamponade almost always requires surgery along with concomitant treatment of the underlying pathology. Colchicine, because of its anti-inflammatory qualities, has the potential to be curative in patients with subacute symptoms and persistent inflammation. When ECP without tamponade is treated first with non-inflammatory drugs and colchicine alone, 84% will have a favorable outcome . The present case likely involved cardiac tamponade, recurrent pericardial effusion, and ECP, perhaps due to both the surgery and the initial secondary infectious pathology. The first treatment was unconventional and invasive, and the second treatment 3 months later was medical, although a surgical option was available if her medical therapy failed and her clinical condition deteriorated.   This case is unique because of its etiology and treatment. The diagnosis was straightforward and uncomplicated. The unusual etiology is likely a combination of the initial treatment of her infectious cardiac tamponade and the subsequent scarring from the pericardiectomy. The role of her previous multiple myeloma and chemotherapy with cardiotoxic drugs is probably minimal since 30 months had passed. The treatment in our center was unusual since our patient was admitted to the CCU 3 months after her pericardiectomy with another suspected cardiac tamponade and ECP. Because her underlying pericardial disease likely represented ongoing inflammation from her previous surgery, she was treated conservatively with colchicine. Her response was favorable, and surgery was avoided, at least temporarily. The important clinical message of this case is to consider medical therapy in stable patients with early-onset ECP and cardiac tamponade when cardiac scaring may be a factor. As in this case, long-term follow-up with cardiothoracic surgery is recommended.   