Cardiac complication spectrum of Behçet disease in Tunisia: A 10-case series: Clinical and therapeutic approach


 Introduction:Cardiac involvement (CI), although rare, remains one of the most severe complications of Behçet Disease (BD).Objectiveto investigate the frequency and spectrum of cardiac involvement in BD and to assess the clinical and imaging features, treatment, and outcomes.MethodsWe retrospectively retrieved the medical records of patients with CI among 220 BD patients admitted to the internal medicine department between 2006 and 2016 who fulfilled the International Study Group diagnostic criteria for the classification of BD.ResultsTen patients were eligible for the study with a sex ratio (male/female) of 8/10. Three cases had 2 isolated episodes of cardiac BD. The mean age when diagnosing the first cardiac episode was 37,3-year-old. The different types of CI were: coronary artery disease (5/10), intracardiac thrombus (4/10) myocarditis (1/10), pericarditis (1/10), myocardial fibrosis (1/10). Vascular involvement was associated to CI in 5 cases (50%). The main symptoms were chest pain (80%), fever (60%), dyspnea (50%), cough (10%) and hemoptysis (10%). The laboratory tests revealed increased inflammatory markers in 5 patients. Medical treatment was based on colchicine and corticosteroid in all patients (100%), anticoagulants in 8 patients (80%), Cyclophosphamide followed by Azathioprine in 9 patients (90%), Azathioprine monotherapy was started in one patient (10%). Antiplatelet and anti-ischemic therapy in 5 patients who had coronary artery disease. The evolution was favorable in 9 cases and marked by severe heart failure and the death of one patient.ConclusionCI despite its rarity, remains an important feature of BD due to the increased risk of mortality and morbidity. Thus, early screening and detection are paramount. Also, imaging has been of great contribution to diagnose such complications and hence indicate the adequate treatment, including immunosuppressant agents.

CI was the presenting symptom of BD in three cases. In fact, the diagnosis was established retrospectively one year after nding an intracardiac thrombus (ICT) in a patient having a congenital heart disease. Also, coronary artery disease was the rst manifestation of BD in 2 other patients. CI appeared during the course of the disease in the other 7 cases and it was up to 2.3 (range 1-9) years after the onset of BD.
The demographic variables and diagnostic criteria are shown in Table 1. Table 1 Demographic characteristics and criteria for Behçet's disease. 3 (30) 5 (50) Vascular involvement whether arterial or venous was found in 5 patients (50%) with 10 manifestations in total: several cases had deep venous thrombosis, including superior/ inferior vena cava thrombosis in two patients, lower limb in one. On the other hand, arterial involvement varied from pulmonary aneurysm (n = 1) to pulmonary embolism (n = 2) and less frequently the disease led to occlusion of some systemic arteries: Right Brachiocephalic artery (n = 2), cerebral artery thrombosis in one patient (n = 1) and superior mesenteric artery aneurysm (n = 1).
On physical exam, we found a cardiac murmur in 3 patients (30%), superior vena cava syndrome in one (10%). Two patients presented with heart failure symptoms (20%), one of them had a history of congenital heart disease (tri-atrial heart).
Electrocardiography was performed in all patients. It showed left ventricle enlargement features in 2 cases (20%), an incomplete right bundle-branch block in one case (10%) and premature ventricular complexes in another (10%). In the acute setting of acute coronary syndrome 4 patients exhibited Non ST-Elevation myocardial infarction (NSTEMI) involvement (in the lateral, posterior and inferior leads (2 patients)) whereas another displayed a posterior ST-Elevation myocardial infarction (STEMI).

Laboratory ndings
Laboratory tests revealed increased in ammatory markers in 5 cases (50%), the average rate of the Erythrocyte Sedimentation Rate and C-Reactive Protein were respectively 57.9 mm/h (5-111) and 47.5 mg/l . Troponin level was signi cantly raised in 5 patients (50%). Bacterial cultures conducted in patients who had fever were all negative. Coagulation pro le was performed in 5 patients, 4 of those had ICT with a lab workup that came back negative, 1 patient with brosing myocarditis showed positive antiphospholipid antibodies (Anti-cardiolipin IgM at 100UI and IgG at 7 UI) along with normal coagulation studies. Plasmatic Homocysteine level was raised in 1 patient (27 µmol/l). Human leukocyte antigen (HLA B 51) tested in all patients was positive in ve (50%).

Imaging features Echocardiography
Transthoracic echocardiography was conducted in 10 patients. It was coupled with trans-esophageal echocardiography in 4, mainly those who had ICT and was performed either for the differential diagnosis or to precisely assess thrombi in the left atrium. In fact, only one patient had a left atrium thrombus in the setting of a congenital heart disease (Cor-Triatriatum), the remaining ones (3) had right atrium and right ventricular thrombi (Fig. 1). Among other echocardiographic nding, we found a left ventricle hypokinesis in patient number 1 ( Table 2) that was eventually diagnosed with a myocarditis and a moderate pericardial effusion (10 mm anteriorly, 15 mm posteriorly) unfolding a pericarditis in patient number 3. Coronary artery disease patients were consistently assessed with a cardiac echocardiography displaying pulmonary artery hypertension in patient number 2 and 8 and normal ndings in the remaining ones. Furthermore, patient number 7 who had the worst prognosis was found with multiple vegetations revealing initially infective endocarditis however he was subsequently found with endomyocardial brosis on histopathological specimen examination.

Computed Tomography
Was conducted in 4 patients. It con rmed the diagnosis of ICT. Furthermore, it was the tool used to scrutinize the vascular system and hence detect any associated lesion.
Computed tomography revealed a right atrial pedunculated mass in accordance with a thrombus in patient number 2. However, it also showed a partial occlusion of the inferior vena cava and thrombosis of the left lobar pulmonary artery with many pulmonary infarcts. Two other patients (number 3 and 4) were found with a double ICT (right atrium and ventricle). In case number 6, Computed tomography exhibited the left atrial intra-cardiac thrombus described in Ultrasound but it also revealed vascular involvement (a partial obstruction of the inferior vena cava as well a pulmonary artery thrombosis and aneurysms).

Cardiac Magnetic Resonance Imaging
Cardiac Magnetic Resonance Imaging was performed in one patient having myocarditis. It showed a myocardial signal intensity increase in T2-weighted images in the antero-lateral and inferior segments of the left ventricle (Fig. 2).

Coronary angiography
This was conducted in 5 patients who had evidence of CAD. Four of them had an NSTEMI and only one had a lateral STEMI, the latter (patient number 9) was found with a tight stenosis of the left circum ex artery. Patient number 5 was hospitalized twice for CAD: an unstable angina pectoris (1st hospitalization) revealed a middle right coronary artery (segment II) aneurysm (Fig. 3). Two years later, he was hospitalized for an inferior NSTEMI revealing an 80% occlusion of the right coronary artery.
Moreover, patient number 10 was found with a tight stenosis of the main left coronary artery and a large aneurysm of the Left anterior descending artery in the context of a lateral NSTEMI. The remaining two patients (number 2 and 8) both bene ted also from primary transluminal coronary angioplasty in the setting of anterior and inferior NSTEMI respectively.

Histopathology
One patient (number 7) had an infective endocarditis following a superior mesenteric artery aneurysm surgery. which was initially treated with antibiotics, then by a valvular replacement. Histologic examination of the specimen showed an endomyocardial brosis with a parietal thrombus.

Treatment
Medical treatment was based on colchicine (1 mg/day) associated to corticosteroids in all cases consisting of 3 daily intravenous pulses of methylprednisolone (15 mg/kg/day) followed by oral prednisone (1 mg/kg daily) gradually tapered over 6 months. Six-month pulses of cyclophosphamide followed by azathioprine were administered in 9 cases (90%). Three patients (30%) had a second 6 month course of Cyclophosphamide due to the recurrence of their CI. Azathioprine monotherapy was started in one patient (10%). Oral anticoagulation treatment was used in 8 cases (80%). Five patients (50%) did bene t from a double antiplatelet therapy [Aspirin-Clopidogrel] in the setting of an acute coronary syndrome. Percutaneous transluminal coronary angioplasty was conducted in 4 patients (20%) and it was successful in two and failed in others. One patient (10%) had a tight stenosis of the main left coronary artery and a large aneurysm of the left anterior descending artery underwent a double coronary artery bypass grafting procedure. Antibiotic therapy was indicated in only 1 patient (30%). Patient number three (10%) with pericarditis received non-steroid anti-in ammatory drugs.
Surgical valvular replacement was indicated in patient number 7 who had an infective endocarditis following a superior mesenteric artery aneurysm surgery.

Outcomes
After treatment, the outcome was marked by severe heart failure and the death of one patient (10%) with an endomyocardial brosis. Furthermore, 2 patients had a relapse of their cardiac involvement; the rest of patients had a favorable evolution. They are all still being monitored with regular clinical and laboratory follow up (Table 2).

Discussion
Behçet disease is a chronic in ammatory 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 in uence on the course of BD and its insidious onset should be addressed. Thus, this paper is among the rst 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][14][15]. Though, the ISG criteria remain the most widely and well-accepted criteria that exhibit relatively decent sensitivity and speci city applicable all across the world [15,16] Cardiac disease was the rst 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 nding 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).  [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 rst 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 nd other lesions (myocarditis, pericarditis, endomyocardial brosis, 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 brosis, 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 ow and then degeneration of vessel wall [28,29].
Thromboembolism mainly triggered by endothelial dysfunction is also a characteristic nding in BD, so endothelium-dependent ow-mediated dilation is diminished causing therefore an increase in vascular in ammation. Furthermore, the associated thrombin and brin release and decreased brinolysis [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 ndings 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 in ltration of capillaries, veins, and arteries of different calibers. When a full-blown vasculitis is present, we might nd brinoid necrosis of vessel wall, endothelial swelling and extravasation of erythrocytes [1,13,27] .
Endomyocardial brosis is a complication rarely seen in BD exhibited by one of our patients. The typical pathologic ndings include a dense brous tissue with neovessels, mononuclear and polymorphonuclear in ltrates, along with calci ed spots [17,34].

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][36][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. ndings [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 nding 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 nd repeated in-stent stenosis, aggressive progress, and elevated in ammation 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 antiin ammatory 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 ndings, 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 in uence: 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 ow, 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 rst, 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 speci c 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 bene cial in this case [1][2][3][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-in ammatory 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 e cient 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-in ammatory drugs.

Endocardial involvement
Endocardial involvement manifests mainly as a valvular dysfunction or more rarely as endomyocardial brosis. It can also be misdiagnosed as infective endocarditis, accordingly if the presentation in incomplete and echocardiographic ndings 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 rst 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 brosis. 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 ine cacy 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 insu ciency 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 brosis 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 brosis 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 brosis 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 ndings 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 in ammation 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 nd 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 nding Laboratory tests typically reveal increased in ammatory markers with a signi cantly elevated Erythrocyte Sedimentation Rate and C-Reactive Protein, and white blood cell count. These nding 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 (anticardiolipinantibody, anti-β2 glycosidoprotein 1 antibody, and lupus anticoagulant), genetic procoagulant factors (Protein C&S de ciency, Antithrombin de ciency, Prothrombin gene mutation, factor 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 con rmed 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 insu ciency in six and mitral valve insu ciency 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 con rmation of ICT and pointed out to some of the vascular system involvement.
Cardiac magnetic resonance imaging has become an ineluctable exam that identi es 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 in ammation [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 in ammatory 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 ndings 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 in ammation. That's why, there is no speci c treatment, the above treatment options are still based on a low level of evidence.

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 antiin ammatory (immunosuppressants, colchicine) agents that offset the in ammatory 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 brosis can be fatal in the course of BD [39] leading to a severe heart failure as seen in patient number 7.

Conclusion
Cardiac involvement, despite its rarity in BD, is among the most severe complications.
It is usually present in young male and may affect the three cardiac tunics and the coronary arteries. Echocardiography remains one of the major radiologic exams that can lead to an e cient early screening of asymptomatic patients along the Silk Route pathway. Furthermore, Cardiac Magnetic Resonance Imaging is also a great tool to highlight some of the complications like myocarditis or ICT. The prognosis of cardiac complications is worse than any other systemic manifestation. Therefore, early administration of colchicine and immunosuppressants agents is paramount and can improve survival rates.

Declarations
Ethics approval and consent to participate This study was approved by the institutional committee of Fattouma Bourguiba University hospital.
Written inform consent was waived due to the retrospective and observational nature of this study.

Consent for publication
Not applicable.

Availability of data and materials
Datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.
Funding: Figure 1 Transthoracic echocardiography in patient number 3: Apical four chamber view (VD: right ventricle, VG: left ventricle, OD: right atrium, OG: left atrium) a) Image of one thrombus in the right atrium, and two thrombi in the right ventricle. b)Trans-esophageal echocardiography exhibiting the right atrium thrombus c) complete resolution of the the thrombi after treatment [67].  Left Anterior Oblique coronarographic incidence in patient 5 showing a totally occlusive thrombotic aneurysmal lesion of the second segment of the RCA.