Author + information
- Received May 24, 2019
- Revision received July 18, 2019
- Accepted July 22, 2019
- Published online October 16, 2019.
- Peter P. Vlismas, MDa,
- Jonas J. Heymann, MDb,
- Charles C. Marboe, MDc,
- Ulrich P. Jorde, MDa and
- Daniel B. Sims, MDa,∗ ()
- aDivision of Cardiology, Montefiore Medical Center, Bronx, New York
- bDepartment of Pathology, Weill Cornell Medical Center, New York, New York
- cDepartment of Pathology, Columbia University Medical Center, New York, New York
- ↵∗Address for correspondence:
Dr. Daniel B. Sims, Montefiore Medical Center, 3400 Bainbridge Avenue, Bronx, New York 10467.
Nonbacterial thrombotic endocarditis is characterized by sterile thrombi on cardiac valves. This report describes the case of nonbacterial endocarditis without pathologic findings of fibrin or platelet deposition. Quadrivalvular endocarditis was found to be due to immunoglobulin M heavy chain deposition. This was a case of nonbacterial, nonthrombotic quadrivalvular endocarditis, which was termed noninfective endocarditis. (Level of Difficulty: Intermediate.)
Nonbacterial thrombotic endocarditis (NBTE) is characterized by the presence of sterile thrombi composed of platelets interwoven with strands of fibrin on cardiac valves (1). No inflammation or microorganisms are detected. The present report discusses what may be the first description of quadrivalvular endocarditis due to the deposition of immunoglobulin M (IgM) heavy chain, with extensive systemic embolization. This study also introduces the term noninfective endocarditis (NIE), which describes the finding of a nonbacterial and nonthrombotic endocarditis.
• To introduce the term, NIE, which describes the finding of a nonbacterial and nonthrombotic endocarditis.
• To make a differential diagnosis for NIE in the setting of a hematologic malignancy.
History of Presentation
A 70-year-old male presented with chest discomfort. On physical examination, he was afebrile and comfortable. Systolic and diastolic murmurs were auscultated throughout the precordium. Electrocardiography showed anterolateral ST-segment depressions. Troponin I concentration was 1.49 ng/ml; white blood cell count was 5.8 × 109 cells/l; hemoglobin was 14.6 g/dl; creatinine was 1.1 mg/dl; and erythrocyte sedimentation rate was 78 mm/h. A transthoracic echocardiogram revealed normal ventricular function and extensive thickening of all 4 cardiac valves and vegetations, measuring 1.5 to 1.7 cm long (Figure 1, Videos 1, 2, 3, and 4).
Hypertension, cerebral microinfarctions, and carotid stenosis
The patient was empirically treated for infective endocarditis, and his chest discomfort was attributed to septic emboli. A transesophageal echocardiogram showed erratically moving echo densities on all 4 valves, with the left atrium and left atrial appendage lined with a fimbriated mass (Figure 1). The ascending aorta had evidence of this process as well. Infectious workup, including cultures for fungus and HACEK organisms (including “Haemophilus, Aggregatibacter [previously Actinobacillus], Cardiobacterium, Eikenella, Kingella”), was negative.
As a result, the working definition of the patient’s condition was changed to NBTE. He was treated with anticoagulant agents with unfractionated heparin. Hypercoagulable and vasculitis workups were unrevealing. Age-appropriate cancer screening results were negative. Serum protein electrophoresis demonstrated 2 monoclonal proteins, IgM lambda and IgM kappa, with associated lambda and kappa Bence-Jones proteins identified by urine protein electrophoresis, raising the possibility of a plasma cell dyscrasia. Bone marrow biopsy was performed. The patient had recurrent episodes of chest discomfort with associated ST-segment depressions. Coronary computed tomographic angiography (Figure 2) revealed calcific plaque in the left anterior descending coronary artery (LAD) and circumflex artery as well as soft plaque in all 3 epicardial vessels with near-total occlusion of the proximal right coronary artery.
The patient was offered valve replacement and debulking with coronary artery bypass surgery, but he declined. His bone marrow biopsy returned nondiagnostic results, so a repeat biopsy was performed. Two hours later, the patient had chest pain with ST-segment elevation and atrioventricular (AV) block. Asystole ensued, and the patient died.
An autopsy demonstrated extensive deposition of amorphous, eosinophilic material on the 4 cardiac valves (Figure 3) and the walls of the atria, pulmonary artery, and aorta. There was embolization to the kidney, spleen, liver, and lungs. The material was found to be nonamyloid IgM heavy chain and lambda light chain without any fibrin or platelets (Figure 4). Atherosclerosis of the coronary arteries with no evidence of rupture was present, with complete occlusion of the LAD by IgM deposition (Figure 5). Bone marrow examination revealed small CD20+ lymphocytes (B-cells) and IgM deposition consistent with an underlying low-grade B-cell lymphoproliferative disorder (Figure 6).
NBTE has been variably referred to as marantic endocarditis, Libman-Sacks endocarditis, and verrucous endocarditis. NBTE is a noninfectious condition marked by the sterile accumulation of fibrin and platelets on the surface of a cardiac valve. It is most often associated with mucin-producing adenocarcinomas or lymphomas, collagen-vascular disease, and hypercoagulable states. The main mechanism for thrombi deposition begins with endothelial damage and the exposure of subendothelial connective tissue to circulating platelets. Current guidelines recommend using intravenous administration of unfractionated heparin or subcutaneous low-molecular-weight heparin in NBTE with systemic or pulmonary emboli as a grade 2C recommendation (2). Valvular surgery has not been evaluated by prospective studies. However, it remains an option in patients with large vegetations, valve dysfunction, or recurrent embolic events while they are receiving anticoagulation.
Thrombus deposition must be present by definition in NBTE. There are only 6 cases of quadrivalvular NBTE reported in published reports, each with evidence of valvular thrombosis (3–8). This report describes what the present authors believe to be the first description of a nonbacterial, nonthrombotic endocarditis of all 4 cardiac valves due to the deposition of IgM heavy chain. There was no evidence of any thrombi at pathology examination. This case demonstrates that NIE is a better descriptor for NBTE, unless there is pathology confirmation of fibrin and platelet deposition.
In the present patient, after infective endocarditis was ruled out with microbiologic data, the diagnosis was changed to NBTE. A search for a hypercoagulable state and solid malignancy did not reveal a cause. The serum and urine protein electrophoreses results suggested that a hematologic malignancy might have been present, particularly a plasma cell dyscrasia. However, the first bone marrow biopsy result was nondiagnostic. Unfortunately, the repeated bone marrow biopsy results were returned after the patient died. The pathology finding of small B-cells extended the underlying differential diagnosis to include Waldenstrom macroglobulinemia, amyloidosis, and light and heavy chain deposition disease (LHCDD).
In addition to the presence of an IgM paraprotein, Waldenstrom macroglobulinemia is characterized by anemia, hyperviscosity, and peripheral neuropathy. An increase of 10% or more of the bone marrow biopsy sample must show the infiltration of small lymphocytes with plasmacytoid or plasma cell differentiation in an intertrabecular pattern (9). These clinical findings and pathologic findings were not present in this case. Primary (AL) amyloidosis is characterized by the deposition of amorphous, eosinophilic material. However, amyloidosis is diagnosed by demonstrating apple-green birefringence under polarized light to Congo red staining which was not seen in this case. Also, cardiac amyloidosis, although associated with valvular thickening, typically presents clinically with a restrictive cardiomyopathy (10). LHCDD is associated with deposition of IgM and lymphoproliferative disorders; however, it is marked by prominent renal involvement with proteinuria and renal failure. When there is cardiac involvement in LHCDD, diastolic dysfunction and conduction system diseases are seen. Although AV blockage was seen immediately antemortem, the other findings of LHCDD were not present. Therefore, the most appropriate diagnosis for this patient is low grade B-cell lymphoproliferative disorder with extensive deposition of paraprotein causing quadrivalvular NIE with embolization to the LAD.
To the best of the present authors’ knowledge, this is the first case of nonbacterial, nonthrombotic quadrivalvular endocarditis caused by deposition of heavy chain IgM. This case highlights the need for a more accurate description of NBTE. Noninfective endocarditis or NIE should be used in cases of cardiac vegetations without evidence of infection or thrombus deposition.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- left anterior descending coronary artery
- light and heavy chain deposition disease
- Nonbacterial thrombotic endocarditis
- noninfective endocarditis
- Received May 24, 2019.
- Revision received July 18, 2019.
- Accepted July 22, 2019.
- 2019 The Authors
- Liu J.,
- Frishman W.H.
- Whitlock R.P.,
- Sun J.C.,
- Fremes S.E.,
- Rubens F.D.,
- Teoh K.H.
- Kawada S.,
- Kuriyama M.,
- Kotani Y.,
- Tsushima S.,
- Tanabe A.,
- Kioka Y.