A rare case of non-infectious mitral valve vegetation in a patient with undifferentiated connective tissue disease

Introduction

Non-bacterial thrombotic endocarditis (NBTE) is a rare clinical disease characterized by endocardial nonbacterial verrucous vegetation and valve thickening. NBTE is frequently referred to as Libman-Sacks endocarditis in earlier literature publications. This condition can be linked to antiphospholipid antibody syndrome (APS), systemic lupus erythematosus (SLE), or malignancy (1). Massive regurgitation brought on by NBTE invasion of the heart valves might impair cardiac function.

In order to extend lives, patients who have advanced to this stage require valve replacement surgery (2,3). This paper reports a patient with mitral valve involvement. After a series of examinations, he was diagnosed with non-infectious valvular heart disease caused by undifferentiated connective tissue disease (UCTD). Following immunotherapy, there was a considerable reduction in mitral valve leaflet thickness and a disappearance of vegetation.

Case presentation

A 78-year-old woman was admitted to Zhejiang Hospital with fatigue accompanied by swelling of both lower limbs for half a month. She had a history of hypertension, coronary artery disease, peripheral neuropathy, and schistosomal liver disease. Post-admission examination revealed anemia and mild edema of both lower extremities. Transthoracic echocardiography (TTE) showed marked thickening of the mitral valve leaflets (Figure 1A; Video 1), with adherence of vegetation near the inner junction (Figure 1B; Video 2). It was accompanied by mild thickening of the tricuspid and aortic valves, biatrial enlargement, and left ventricular diastolic hypoplasia. Laboratory results showed a white blood cell count of 5.7×10⁹/L and a platelet count of 82×10⁹/L. The patient had no fever, and the results of routine blood tests and blood cultures were negative. Bacterial endocardial redundancy was not considered; no clear pathological cause was identified at this stage. Upon review of the relevant literature, NTBE emerged as a potential cause, and the patient underwent further relevant investigations. Serologic tests showed antinuclear antibody (ANA) positive ++, anti-strikepoint B protein antibody positive ++++, anti-mitochondrial M2 antibody positive ++++, and SLE-related antibody negative. Blood immuno solid phase electrophoresis showed IgM and K chains positive. Electromyography suggested evidence of neurogenic damage to the right and left bunion abductor and tibialis anterior detector muscles. Given the ANA test results and the patient’s prior Raynaud phenomenon, connective tissue disease was considered, but SLE and APS were excluded. Meanwhile, the patient had thrombocytopenia, anemia, and peripheral neuropathy. Consequently, the patient was diagnosed with UCTD. Accordingly, the diagnosis of this patient took a new direction. We guessed that the heart valve lesion might be caused by the patient’s autoimmune system abnormality. Therefore, she was treated with prednisone tablets and Paeonia lactiflora capsules for immunotherapy. Other basic treatments were provided to manage her other diseases, such as improving osteoporosis, and replenishing electrolytes. After 1 month of treatment, the patient’s symptoms of fatigue were reduced. Laboratory test platelet count rose to 98×10⁹/L. Serologic tests showed ANA positive ++, anti-strikepoint B protein antibody positive +++, and anti-mitochondrial M2 antibody positive +++. TTE suggested that the patient’s mitral valve leaflet thickening was significantly reduced (Figure 1C; Video 3), mitral valve vegetation had significantly disappeared (Figure 1D; Videos 4,5), and left ventricular diastolic function had returned to normal, which reinforced our suspicion of UCTD. Unfortunately, we were unable to perform transesophageal echocardiography (TEE) due to patient intolerance.

Figure 1 TTE showed the changes of mitral valve before and after treatment. Before treatment: (A) the LV long axis section of the TTE suggests thickening of the mitral valve (7 mm); (B) the LV short axis section of TTE suggests vegetation formation in the posterior mitral lobe (25×8 mm, white arrow). After treatment: (C) the LV long axis section of TTE suggests that the mitral valve is significantly thinner than the anterior one; (D) the LV short axis section of TTE indicates the disappearance of mitral vegetation. LA, left atrial; LV, left ventricular; RV, right ventricular; AO, aortic; MV, mitral valve; TTE, transthoracic echocardiography.

All procedures performed in this study were in accordance with the ethical standards of the Medical Ethics Committee of Zhejiang Hospital (No. 2022KY463) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient for publication of this article and accompanying images and videos. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Redundancy in the mitral valve favors infective endocarditis. In this case, once it had been identified, its etiology needed to be clarified. Despite the patient’s inability to tolerate TEE, our TTE examination was adequate to determine the involvement of the mitral valve. We referred to the diagnostic thinking of endocardial vegetation required by the 2023 ESC Endocarditis Management Guidelines (4) and performed a series of laboratory investigations on the patient in compliance with the guidelines. In this case, the patient did not have fever or other symptoms of infection. After several blood cultures and routine blood tests that did not suggest bacterial infection, infectious endocarditis (IE) was eliminated from being the cause of the condition. A non-infective mitral valve redundancy needed to be considered (1,4). NBTE is extremely uncommon and is often referred to as Libman-Sacks endocarditis, marantic endocarditis, and thrombotic or verrucous endocarditis (1). However, the exact pathogenesis of NBTE is unknown. It is theorized to be related to immune complexes, hypoxia, hypercoagulability, and carcinoma. The development of NBTE may begin with endothelial injury in patients with hypercoagulability, which is mainly seen in malignant tumors (adenocarcinomas predominantly) and connective tissue disorders (CTDs) such as SLE and APS (1,2,3,5).

The patient’s laboratory results were positive for CTDs, and in combination with a history of Raynaud’s phenomenon and peripheral neuropathy, we achieved a clear diagnosis of CTDs. However, there were no specific antibodies in the serology that would have allowed for a diagnosis of a specific connective tissue disease such as SLE or APS. Connective tissue disease is an umbrella term for a variety of disorders, each of which has specific diagnostic criteria. However, if a patient’s signs and symptoms do not meet any of these diagnostic criteria, a diagnosis of UCTD may be made. The presence of UCTD has been common in previous clinical experience. Most of these patients will have milder clinical manifestations, and some will progressively progress to SLE or systemic sclerosis (SSc) (6-8). The impact of connective tissue disease on the heart is multifaceted. It may lead to increased reflux of different valves in patients, pericardial effusion, and even left ventricular hypertrophy and cardiac insufficiency (6,8). Unfortunately, there are no guidelines or expert consensus related to cardiac ultrasonography for this specific patient group with connective tissue disease. We need to rely on clinical experience for identification and diagnosis. Eventually, after reviewing the literature and deep thinking, the valvular disorder in this patient was considered as NBTE and most likely Libman-Sacks endocarditis. NBTE is usually characterized by valve invasion, most commonly in the mitral valve, and it can also lead to multiple valve involvement. Valve abnormalities can be in the form of vegetation or thickening of the valve. Some patients may experience massive regurgitation of the valve, or worse, vascular embolism (3,5,9). However, in this case, the cardiac function of the patient was mildly affected. The mitral valve did not show a large amount of regurgitation, the systolic function of the heart was not yet affected, and only the diastolic function of the left ventricle was mildly limited. Patients with severe valvular damage are often treated with valve replacement, whereas those in the early stages of valvular dysfunction who are not significantly affected are usually treated with glucocorticoids with good results (10-13). The patient received immunotherapy with prednisone tablets and Paeonia lactiflora capsules. After 1 month, TTE revealed a significant reduction in mitral leaflet thickening and a significant disappearance of mitral valve vegetation. The patient’s symptoms of fatigue were reduced, and the laboratory test platelet count tended to be normal. Serologic tests showed a slight decrease in titers of relevant antibodies. Paeonia lactiflora is a traditional Chinese medicine in China. It has been used to treat inflammation, pain, and immune diseases for thousands of years. Due to its mild effect, many indications, and few adverse reactions, Paeonia lactiflora extract is still one of the important drugs for the treatment of rheumatoid arthritis (RA), SLE, and other immune diseases in China (14). Therefore, we added Paeonia lactiflora capsules to the treatment regimen and the patient benefited from it.

Obviously, the patient’s heart involvement due to connective tissue disease was detected in time, and the implementation of effective treatment prevented the necessity for mitral valve surgery. Patients with NBTE are usually asymptomatic in the early stages, which often prevents its timely detection. By the time a patient develops symptoms, the heart function and valvular damage is not promising (1,11-13). Therefore, the valve involvement should be resolved as early as possible before the NBTE causes impaired cardiac function. The impact of the underlying disease process should be controlled or mitigated. TTE is the imaging modality of choice. It is noninvasive, convenient, and can detect cardiac involvement at its earliest stages. TEE can be used to further confirm the extent of valvular damage when necessary (2, 9,15).

Conclusions

NBTE is a rare condition, and it is usually associated with connective tissue disease or malignancy. The patient in our case was successfully diagnosed due to timely detection by TTE and achieved a good outcome with prompt immunotherapy. Therefore, we believe that the possibility of cardiovascular involvement should be considered in patients with connective tissue disease who experience exacerbations, and the role of TTE should not be overlooked.

Acknowledgments

Funding: This work was supported by Zhejiang Health Science and Technology Project (No. 2022KY463).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1851/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Medical Ethics Committee of Zhejiang Hospital (No. 2022KY463) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient for publication of this article and accompanying images and videos. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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