Behçet disease is a chronic inflammatory disease of unknown origin that might have been described by Hippocrates [8] but it was brought to the attention of the modern medical community by the Turkish dermatologist Hulusi Behçet in 1937 [6, 9].
This disease is characterized by a relapsing course of oral aphtae and multiple systemic manifestation including genital aphtae, ocular and neurologic disease, respiratory, gastrointestinal and cardio-vascular manifestations [3, 4, 10]. Although the CI remains rare in most cross-sectional studies, its prognostic influence on the course of BD and its insidious onset should be addressed. Thus, this paper is among the first to focus on cardiac manifestation in the North African region [11].
Behçet disease criteria
There is no pathognomonic test to diagnose BD. It is best assessed based on clinical grounds in the context of recurrent aphthous ulcerations along with systemic manifestations. As a result, we used the diagnostic criteria published by the International Study Group in 1990 [12]. In 2006, The International Team for the Revision of the International Criteria for Behçet's Disease had established new criteria in an effort to improve sensitivity; therefore, vascular involvement was added while oral aphthae were no more mandatory for diagnosis [13–15]. Though, the ISG criteria remain the most widely and well-accepted criteria that exhibit relatively decent sensitivity and specificity applicable all across the world [15, 16]
Cardiac disease was the first manifestation in nearly 30% of BD cases with CI in large cohort studies [11, 17]. Accordingly, the diagnosis of cardio-BD should be considered even in cases when the classical criteria are absent, especially in young male patients residing at the Silk Road route. In these cases, a detailed analysis of the heart and large vessel structures are recommended by imagery and an adapted follow-up should be implemented [2].
Epidemiology
Cardiac involvement is a rare finding in BD ranging between 0.13–16.5% of patients according to previous studies. This frequency varies depending on the ethnic groups and geographic parameters [1–3, 17–23] (Table 3).
Table 3
frequency of cardiac involvement in Behçet Disease in the literature
Author (country) | Year | Number of the patients with BD | Cardiac involvement frequency |
Lakhanpal(Japan) [19] | 1985 | 170 | 16.5% |
Assaad-Khalili(Egypt) [24] | 1993 | 350 | 15% |
Gurler (Turkey) [21] | 1997 | 2147 | 0.13% |
B’chir Hamzaoui (Tunisia)[22] | 2006 | 519 | 2% |
Geri (France) [17] | 2012 | 807 | 6% |
Zhang (China) [23] | 2013 | 334 | 8,1% |
Wang(China)[3] | 2016 | 626 | 1.9% |
Our study | 2020 | 220 | 4.54% |
CI occurred mostly in young males in our study. Likewise, Wang et al. reported [3] that BD patients with ICT had a sex-ratio of 9/12 (75% males) with a mean age of 33.5-year-old. According to these observations, CI tends to occur more often in young male adults.
The frequency of different types of CI varies from one study to another. This is among the very first study with a high incidence of coronary artery involvement with 50% of patients affected. In addition to that, 40% had ICT and only sporadically did we find other lesions (myocarditis, pericarditis, endomyocardial fibrosis, etc.). In contrast, in Geri et al. study, 807 French BD cases were included with 48 patients having CI; depicting 38% as pericarditis, 26% as endocarditis, 19% as ICT, 17% as myocardial infarcts, 7% with endomyocardial fibrosis, and 2% with myocardial aneurysm [17].
Pathophysiology, histopathology
There is no known underlying cause of BD. As any autoimmune disease the disorder might be due to an aberrant immune response in genetically predisposed individuals. Hence the positive correlation of HLA B51 with BD activity and severity [25].This abnormal immune reaction might be triggered by exposure to some viral or bacterial epitopes [26].
Many clinical manifestations including cardiovascular involvement are thought to be due to vasculitis [27]. In fact, activated neutrophils cause excessive oxidative stress through an increased level of free radicals like superoxide anions and lysosomal enzymes. This happens along with a disequilibrium of scavenging enzymes which eventually leads to destructive effects [15]. Indeed, vasorum occlusion and transmural necrosis in the walls of the large muscular arteries ensues leading to deterioration of blood flow and then degeneration of vessel wall [28, 29].
Thromboembolism mainly triggered by endothelial dysfunction is also a characteristic finding in BD, so endothelium-dependent flow-mediated dilation is diminished causing therefore an increase in vascular inflammation. Furthermore, the associated thrombin and fibrin release and decreased fibrinolysis [28, 30] will eventually lead to heart and vessel lesions [31, 32].
The dysfunction of autonomic nervous system has also been suggested as an etiology especially in the cases of silent myocardial infarction [33].
The role of antiphospholipid antibodies, especially anti-cardiolipin, is still controversial in BD [34]. In some studies, these antibodies have been suggested to have a causative role in the intra-cardiac thrombi formation e.g. in Wang et al. study, among 7 BD patients with ICT, lupus anticoagulant was detected in 2 of them [3] which is in agreement with our findings as anti-cardiolipin antibody was positive in one patient. hyperhomocysteinemia has also been advocated in some papers as being a predictor of BD activity; even more it might contribute to the pathogenesis of the disease which could explain its positivity in our series [18] .
Histopathology
Classically, BD related lesions show a necrotizing leukocytoclastic obliterative perivasculitis associated with a venous thrombosis and a lymphocytic infiltration of capillaries, veins, and arteries of different calibers. When a full-blown vasculitis is present, we might find fibrinoid necrosis of vessel wall, endothelial swelling and extravasation of erythrocytes[1, 13, 27] .
Endomyocardial fibrosis is a complication rarely seen in BD exhibited by one of our patients. The typical pathologic findings include a dense fibrous tissue with neovessels, mononuclear and polymorphonuclear infiltrates, along with calcified spots [17, 34].
Clinical features
Diagnosis time lag
Cardiac involvement can be the cardinal manifestation of BD or can appear after the diagnosis by months or even years [3, 17, 35–37].
In our study, CI was the presenting manifestation of the disease in three cases (30%), which is consistent with previous results, as in Geri et al. findings [17], where they reported 32.7% of patients having primarily cardiac BD. This involvement is often silent; it could be screened by imaging i.e. angiography or holter monitoring in asymptomatic patients when the diagnosis of BD is made [33, 38]. In the symptomatic patients, clinical features differ according to the type of the involvement.
Coronary artery disease
Coronary artery involvement in BD is extremely uncommon, thus the importance of our study to highlight the target population characteristics and the prognosis of such involvement. As previously described, this affects mainly young male patients without cardiovascular risk factors living across the ancient silk road such as Turkey, Middle East, Mediterranean basin and other Asian countries [39, 40]. This involvement is exceptionally rare due to the wide presenting symptoms and perhaps the silent form that goes under diagnosed. As a matter of fact, according to Turkolmez et al. study [41] silent myocardial ischemia has been found in 19,5% of BD patients compared to 2.9% of sex- and age matched of healthy control group; other symptoms include angina pectoris or congestive heart failure [11, 17, 37, 42, 43].
Usually coronary artery disease (CAD) is a complication occurring in patients already diagnosed with BD, however as showed by two cases in our series it can be the initial presentation revealing the disease [44] especially in the Mediterranean basin as oral aphtosis is a common finding not always pointing to BD. Lesions affecting coronary arteries include stenosis, occlusion, in-stent stenosis, aneurysm and pseudo aneurysm [37, 43, 45, 46]. The course of CAD in young patients can also be a feature unfolding the diagnosis, especially if we find repeated in-stent stenosis, aggressive progress, and elevated inflammation markers. Recently, Ma et al [46] reported a middle aged male, in whom BD was revealed by an abdominal aorta pseudo aneurysm. This patient had coronary artery lesions 10 years before the diagnosis of BD with repeated in-stent bypass graft restenosis despite a good control of cardiovascular risk factors and an intensive medical treatment [45, 46]. Hence, the urge of developing new screening methods for an early diagnosis.
Management of CAD in the context of BD can be very challenging since the guidelines are not yet well established, for example anticoagulant and thrombolytic may precipitate bleeding in aneurysms [47] and corticoid pulses can curtail the heart healing process and hence rendering it more prone to rupture [39, 48]. In addition, mechanical manipulation of the coronary vessels through surgery or angioplasty while the vasculitis is still ongoing is considered very risky and can worsen the prognosis even more [49]. Therefore, patients must receive adequate medical therapy to minimize the vasculitis and to improve outcomes [50]. However, despite the therapeutic burden of the disease, classic measures are still implemented with an early start of medical therapy and an optimal control of cardiovascular risk factors [2, 45]. The cornerstone of CAD treatment in the setting of BD remains the early implementation of anti-inflammatory agents as highlighted in Ma et al. study [46]. Consequently, non-use of corticosteroids and immunosuppressant exposes the patient to the extension and the recurrence of the complication.
Intracardiac thrombus
Compared to venous thrombi, ICTs are relatively uncommon in BD.
According to our findings, only 1.8% of the original BD pool were affected which is consistent with the prevalence in Wang et al. study [3], noted in 1.9% among 626 BD patients. ICT was the second cardiac complication is our series (40% of cases) and this can be explained by the geographic influence: The Mediterranean basin being an endemic area [11]. Usually, it occurs in male aged < 40-year-old without adequate immunosuppressive therapy within 10 years of the diagnosis [3], but It might also be the presenting sign of BD as observed in patient number 6.
In agreement to previous studies [1, 37], ICTs involved the right heart chambers more often (3 vs 1 left atrial thrombus) than the left, perhaps because some are extended thrombi from the vena cava and also because the lower pressure in the right heart predisposes for stasis of blood flow, one of Virchow triad criteria. Furthermore, there is a predilection to involve ventricles more than atriums [4, 9] but the reason is still unclear [10, 51]
Clinically, the main symptoms are palpitation, hemoptysis, cough and dyspnea. Also, fever and heart failure symptoms might be present [1, 39]. ICT can also be revealed by a pulmonary embolism as seen in one of our patients, or embolic strokes caused by emboli passing through the patent foramen ovale. Sometimes patients are asymptomatic and ICT is then diagnosed only by an ultrasound screening [3, 18]. Considering differential diagnosis, myxoma is among the first, however in the context of BD we should primarily suspect an ICT in front of a right ventricular mass compared to the frequent left atrial location of cardiac tumors [9, 52]. For that reason, imaging is a major tool to narrow down the diagnosis. In addition, right heart chamber thrombus is highly specific for BD thus, the diagnosis should be on the differential even though other symptoms are absent [9, 10]. ICT are also often reported to be associated with deep vein thrombosis and pulmonary artery aneurysms [1, 4, 9, 53].
Until now no guidelines or large cohort with evidence based medicine have been proposing a standard treatment, in fact it mainly depends on the discretion of physicians and habits of every treating center [39]. What is primarily used is a combination of anticoagulants and immunosuppressive drugs and that’s what we opted for in our tertiary referral center. Other hospitals, also use remotely thrombolytics when the clot is mobile [2].
Some studies suggest that unlike the common thrombotic diseases, BD thrombosis is positively correlated with the extent of vasculitis and hence the rationale favoring the use of immunosuppressive drugs [3] .
When associated to a pulmonary arterial aneurysm as in one of our patients, ICT must be treated with an intensive immunosuppressive treatment. However, anticoagulant and antithrombotic therapy should be given cautiously due to the risk of bleeding. Trans catheter embolectomy could be beneficial in this case [1–4]. Besides, the “European League Against Rheumatism” recommends the use of cyclophosphamide in the cases of ICT and pulmonary arterial aneurysm [54].
Severe ICT i.e. causing heart failure requires surgical excision, but an isolate surgery does not lead to complete resolution, it must be associated to immunosuppressive drugs, steroids, and warfarin [1, 52].
Pericardial involvement
In contrast to our study, pericardial involvement has been reported as the most common manifestation representing respectively 40% and 38.5% of CI in Wechsler et al. and Geri et al. studies [17, 20]. This complication can also be the cardinal presentation of BD and can be recurrent but rarely does it lead to further complications such as constrictive pericarditis [17].
Pericardial effusion manifests with a stabbing chest pain, fever and dyspnea. An asymptomatic pericardial effusion can be detected by electrocardiographic abnormalities or a systematic echocardiography [2, 43, 55, 56].
Moderate pericarditis, can be treated with non-steroid anti-inflammatory drugs and less frequently immunosuppressive agents are indicated [4]. Emergency pericardiocentesis is required if the pericarditis is complicated by a tamponade [2]. Moreover, colchicine, indicated in all cases of BD, has been reported as an efficient treatment of pericarditis whatever its etiology, even when it is recurrent [57]. Our patient had initially a favorable evolution with a therapy combining Colchicine and non-steroid anti-inflammatory drugs.
Endocardial involvement
Endocardial involvement manifests mainly as a valvular dysfunction or more rarely as endomyocardial fibrosis. It can also be misdiagnosed as infective endocarditis, accordingly if the presentation in incomplete and echocardiographic findings are present Major Duke criteria can be met resulting eventually in a delayed diagnosis, a worse prognosis and sometimes complicated surgeries[11, 39].
For discrimination purposes endocarditis and vasculitis in BD are recurrent and acute rather than persistent and chronic. One of our patients had a valvular replacement and antibiotic therapy after being diagnosed first with infective endocarditis as a complication of a superior mesenteric artery aneurysm surgery. Then, he was hospitalized a second time for a severe heart failure due to endomyocardial fibrosis. The course was fatal and culminated with the death of the patient. This could again be due to the confounding diagnostic dilemma of infective endocarditis. That’s why in valvular pathology, the diagnosis of infectious endocarditis is generally excluded by the inefficacy of antibiotics treatment, hence a therapy combining corticosteroids and immunosuppressive agents is then indicated.
As far as valvular involvement is concerned, aortic and mitral valves are the most affected valves [38] indeed aortic valve insufficiency is ranked as the second most common cardiac complication in Gueri et al. study [17]. Clinically, valvular lesions can be presented as an isolated acute or subacute manifestation or as a valvular regurgitation diagnosed by echocardiography.
Endomyocardial fibrosis is an exceptional but a severe complication of BD. It is usually presented by right heart failure symptoms and diagnosed during specimen microscopic examination as conducted in our tertiary center. This could be the sequelae of vasculitis involving the myocardium, endocardium, or both, complicated by mural thrombus [17].
For our patient, endomyocardial fibrosis could also be explained by the increased antiphospholipid antibodies that have contributed to the pathogenesis of this complication.
Management of endocardial involvement is controversial, due to the wide differential diagnosis and the frequent absence of all BD criteria. For instance, Jeong et al. [58] found that patients operated for aortic regurgitation without considering their underlying BD had a fatal outcome (47.3% mortality rate). Endomyocardial fibrosis in usually treated with colchicine, immunosuppressive agents [2] however, if it is complicated by heart failure surgical excision can be successful.[59]
Myocardial involvement
isolated myocarditis is rarely reported in BD. It was found in 2 patients among 28 with CI in BD in a Japanese autopsy review [19] and only one case among 52 European patients in Geri et al. study [17]. The diagnosis is suspected in front of a patient with symptoms of a heart failure, conduction abnormalities, or kinetic abnormalities in the ultrasound [56, 60].
It seems that myocardial involvement’s frequency is underestimated, the prevalence is reported to be more important in the studies where patients underwent a systematic imaging screening exam: an echocardiography or a scintigraphy [11, 18].
Treatment is mainly based upon the management of heart failure, and treatment of arrhythmias and immunosuppressive therapy should always be implemented when BD is highly suspected.
Associated systemic vascular involvements
Our findings are in accordance with previous papers, as patients with cardiac involvement had frequently affected vessels [3]. This might be explained by similar pathophysiologic processes that are positively correlated with inflammation and disease activity [3, 54]. Behçet disease is remarkable for its ability to involve different calibers of blood vessels, on both the venous and arterial sides of the circulation [1–4, 23, 38].
According to previous studies, the venous system is usually the most affected [54], 50% of our patients had venous lesions. This involvement was frequently associated to ICT. Indeed, Wang et al. reported that 75% of patients with ICT had inferior or superior vena cava thrombi, hence the assumption that right heart ICTs prevalence might be due to extension of venous thrombi [3].
Arterial involvement, is also common in BD patients with heart complications and is usually expressed by aneurysms, pseudo aneurysms or stenosis [11, 42].
Pulmonary involvement is a systemic involvement frequently associated to cardiac complications especially along ICT [1]. Pulmonary embolism was found in 2 out of 10 patients in our study; Despite being rarely reported in literature because of the strongly adherent tendency of clots in deep veins [46]. This could be explained by the migration of ICTs instead. On the other hand, Mogulkoc et al. [37], found that 12 out of 25 patients with ICT (48%) had pulmonary arterial aneurysms (PAA) which are an important cause of massive hemoptysis[11, 42] as seen in one case in our study. As a result, the association between PAA and ICT in BD increases the risk of hemorrhage and especially of hemoptysis by anticoagulant use [60, 61].
Electrocardiography
It is not uncommon to find abnormalities like atrioventricular block during BD. It is reported in 23.1% in Gao et al., and according to the same study prompt management is recommended even with mild conduction disturbance [62, 63]. Also arrhythmia such as paroxysmal atrial tachycardia, complex ventricular arrhythmias, premature ventricular beat, or conduction defects as QT dispersion can be found [11, 55]
Laboratory finding
Laboratory tests typically reveal increased inflammatory markers with a significantly elevated Erythrocyte Sedimentation Rate and C-Reactive Protein, and white blood cell count. These finding could guide the diagnosis of BD in front of cardiac complications without cardiovascular risk factors in a young Mediterranean male [1, 3, 4, 38]. Furthermore, troponin level can be elevated in the case of myocardial ischemia but Pro-BNP value can be raised in several forms of CI [2].
Autoimmune and thrombophilia screening including antiphospholipid antibodies (anti-cardiolipinantibody, anti-β2 glycosidoprotein 1 antibody, and lupus anticoagulant), genetic procoagulant factors (Protein C&S deficiency, Antithrombin deficiency, Prothrombin gene mutation, factor Ⅴ Leiden mutation) is frequently performed and is usually negative[1, 3, 4]. Nevertheless, it could show positive antiphospholipid antibodies whose correlation with CI is controversial [3, 34].Human leukocyte antigen (HLA B51), positive in 5 out of 10 patients, is usually screened. Many studies have confirmed the evidence linking HLA-B*51 with susceptibility for BD, but no study has demonstrated its relationship with CI [51, 64].
Imaging features
Echocardiography was performed in all our patients, whether transthoracic or trans-esophageal, is a simple, available and a harmless exam. It contributes to identify early cardiac lesions and to appreciate their severity and extent even in asymptomatic patients [11, 22, 38]. Consequently, echocardiography is often recommended in BD patients by many authors. In the study of Ulusan et al. [65], echocardiography was performed in 38 asymptomatic BD patients. It detected aortic valve insufficiency in six and mitral valve insufficiency in three patients. Therefore, Echocardiography remains a paramount tool used not only for CI screening in BD but also for early diagnosis and treatment indications.
Computed tomography can help in detecting ICT showing amorphous, homogeneous, medium and hyperdense mass. It is also a vascular involvement screening tool remotely revealing arterial aneurysms, venous thrombosis or pulmonary embolism [1, 4, 42]. The main drawback of Computed tomography, is that it exposes to radiation and contrast medium complications. It was conducted in 3 of our patients and led to the confirmation of ICT and pointed out to some of the vascular system involvement.
Cardiac magnetic resonance imaging has become an ineluctable exam that identifies and appreciates the extension of CI in BD. This exam is usually indicated in myocarditis or ICT. It aids in having an objective assessment of myocardial inflammation [66]. Cardiac magnetic resonance imaging also detects functional and morphological abnormalities as well as tissue pathology as diagnostic features of myocarditis. Furthermore, it determines the regional distribution and extent of reversible and irreversible myocardial injury [66]. That’s why, Cardiac magnetic resonance imaging was critical in detecting myocarditis in one of our patients. Secondly, it can be a relevant tool in differentiating ICT from a cardiac tumor i.e. myxoma, as thrombus is avascular without contrast uptake [3, 52]. In Wang et al. study[3], Cardiac magnetic resonance imaging was performed in four patients with ICT and revealed 3 masses with isointense signal on T1-weighted image and low signal on T2 weighted images, delayed enhancement was depicted in one patient who had organized clots associated with inflammatory cells.
Coronary angiography is the gold standard in the case of CAD as it can identify not only occlusions but also aneurysms which are characteristic findings of BD. These latter could have a saccular or fusiform aspects in angiography [51]. However, if conventional angiography is chosen it is important to be careful with its complications like pseudoaneurysmal formation and infectious risk with femoral puncture. As a result, non-invasive methods such as ultrasonography, magnetic resonance and computerized tomography angiography should be preferred primarily for diagnosis [28].
Treatment
Generally speaking, the aim of the CI in BD’s treatment is to alleviate symptoms, and to prevent permanent organ damage by repressing inflammation. That’s why, there is no specific treatment, the above treatment options are still based on a low level of evidence.
Consequently, pharmacological agents including colchicine, corticosteroids, immunosuppressive agents (cyclophosphamide, cyclosporine, azathioprine), more rarely tumor necrosis factor-α inhibitors, interventional and surgical treatment are the main options we have [1, 2].
Prognosis
Overall, survival in BD patients with CI is unfavorable as compared with those who don’t. Global mortality of BD is estimated at 5.4% in 5 years, and reach 15.4%-20% in such a complication[7, 24, 42]. Better prognosis was found in the cases of an earlier diagnosis especially with the early introduction of anti-inflammatory (immunosuppressants, colchicine) agents that offset the inflammatory burden [2, 17, 42]. Vascular aneurysm rupture is reported to be the most common cause of mortality. Hence, poor prognosis was reported in the case of BD associated to CAD as it can lead to severe coronary aneurysms. Accordingly, 25% of mortality was due to CAD in Geri et al study [17]. Also, endomyocardial fibrosis can be fatal in the course of BD [39] leading to a severe heart failure as seen in patient number 7.