HVD in APS patients is defined by the presence of valve lesions and/or moderate to severe valve dysfunction in the absence of a history of rheumatic fever or infective endocarditis (1). Valvular involvement was the earliest reported cardiac manifestation of APS (13) and is the most common cardiac manifestation of APS. It includes valvular thickening and valve vegetations (also referred as Libman-Sacks endocarditis) (14). Valve lesions in APS are characterized by localized valve thickness >3 mm involving the proximal or middle portion of the leaflets and irregular nodules on the atrial area of the mitral valve or the vascular side of the aortic valve are typical. The most commonly affected valves are the mitral valve, followed by the aortic valve (15, 16). In general, different studies have shown that approximately one third of PAPS patients have HVD when evaluated by transthoracic echocardiography (TTE), and that the prevalence was significantly higher compared with healthy individuals in whom valve lesions were evident in 0 to 5 percent (14, 17–23). However, the prevalence of HVD in PAPS ranges from 10% to more than 60% in various studies (24). Due to the different imaging techniques (transthoracic [TTE] or transesophageal [TEE] echocardiography) utilized for assessing HVD. Another important point is the comparison of HVD prevalence in PAPS and SLE-associated APS. Only few studies have directly compared these two groups. It was shown that the average prevalence of valve involvement was found to be significantly higher in the secondary APS group (41 vs. 27%, P = 0.007) (25, 26). In parallel, SLE patients who are aPL-positive compared to aPL- negative exhibit a significantly greater prevalence of valvular abnormalities (27). In a meta-analysis of aPL-associated HVD in SLE patients, the risk of HVD was higher in patients with LAC or IgG aCL (OR 6) compared with IgM aCL (OR 3) (23). Moreover, nearly 90% of SLE patients with HVD had positive aPL compared to 44% of SLE patients without HVD. Valve impairment in PAPS is usually asymptomatic but it can lead to significant dysfunction. A progression to severe valvular regurgitation requiring surgery is found in ~4–6% of APS patients with HVD (15). A history of arterial thrombosis increases the co-morbidity of HVD in APS patients (51%) compared with a history of venous thrombosis (42%) (20, 21, 28, 29). Aortic valve lesions, confer an increased risk of stroke (27). A retrospective study of 284 APS patients, 159 of whom diagnosed with PAPS, found significant correlations between HVD and CNS manifestations (epilepsy, migraines, cerebrovascular accidents, and transient ischemic attacks), while patients with SAPS had no such correlations. Thus, CNS manifestations in PAPS may occur in the presence of valvulopathy (25).

The histopathological characteristics of aPL-associated valvulopathy are non-specific and include fibrosis, calcification, vascular proliferation, verrucous thrombosis on endocardial valvular surfaces, and thrombosis of intravalvular capillaries (19, 28, 30). Microscopy of deformed heart valves from APS patients revealed depositions of immunoglobulins including aCL (mainly IgG) and complement components, located along the exterior of the leaflets and cusps. Such deposits were not evident in control valves from aPL-negative patients and APS patients without valve involvement (31). Possibly, aPL may cause a sub-endocardial inflammatory process through an interaction with antigens on valve surfaces (32). The mechanisms of thrombosis and inflammation subsequently lead to fibrosis and calcification and eventually to valve deformation (19). There is some evidence in the literature of an association between the valve lesions in rheumatic fever (RF) and the presence of aPL. A study which evaluated the serum of 90 patients with RF and of 42 patients with APS, showed that 24% of patients with rheumatic heart disease had positivity for anti-β₂GPI and that patients with APS had anti-streptococcal activity, recognizing the M protein in 16.6% of cases. The authors concluded that there is considerable overlap of humoral immunity, supporting the hypothesis of common pathogenic mechanisms in development of valvular manifestations in APS and RF (33). Another work showed that 80% of RF patients were positive for aCL antibodies during active phase of the disease (34). More studies are needed to evaluate a potential association between RF-associated valve lesions in RF and the presence of aPL.

Many prevalent conditions can impair myocardial function (e.g., diabetes mellitus, hypertension, IHD). Thus, distinguishing primary myocardial disease from other common causes of myocardial injury is quite challenging. Antibodies in the myocardium may cause ventricular dysfunction in APS. Coronary artery thrombosis and/or microvascular thrombosis may also lead to APS-related ventricular dysfunction by causing myocardial ischemia (70, 71).

Patients with SLE-APS displayed more left ventricular (LV) systolic dysfunction as compared with PAPS (72, 73). In a comparative evaluation of diastolic filling by echocardiography in 10 PAPS patients and matched healthy controls, diastolic dysfunction in PAPS patients was more prominent. All subjects were free of any cardiac risk factors or pathology that could lead to diastolic dysfunction. On the other hand, LV systolic function was normal in all these patients (74). The abnormal LV filling patterns seen in APS may be a preceding sign of myocardial involvement and systolic dysfunction. The mechanism in which aPL might cause impaired diastolic function directly is not fully understood.

A few cross-sectional studies have shed light on echocardiography findings of the right heart chambers in APS and SLE (75, 76). These studies have shown that in APS, right ventricular (RV) diastolic dysfunction occurs as a primary process independent of concomitant HVD or systolic dysfunction. In a large cohort, a more severe RV diastolic impairment was demonstrated in patients with PAPS compared with SAPS. In PAPS, the right ventricle might be involved more frequently (76). Some reports indicate that endomyocardial fibrosis may lead to severe right heart failure in APS patients (71).

Diffuse cardiomyopathy is a less frequently reported manifestation in APS. However, there are several reports describing a possible histopathological association between dilated cardiomyopathy and the presence of aPL, in the absence of conventional risk factors (13, 76–79). In these cases, autopsies revealed widespread occlusive microthrombosis of small myocardial arterioles and areas of micro-infarction surrounding affected arterioles, which led to extensive myocardial necrosis. On histopathological examination there were no vasculitic characteristics thus supporting the idea that aPL induces a direct thrombotic effect rather than by means of underlying defects in blood vessel walls (18). In one study, there was a significant correlation between high titers of aCL IgM and heart failure (6).

Venous thromboembolisms are among the most common manifestations of APS, with a very high recurrence risk. APS-associated pulmonary embolism (PE) frequently leads to chronic thromboembolic pulmonary hypertension (CTEPH) (80), which is a prevalent non-valvular cardiac manifestation of APS. The sole presence of PHT in SLE patients worsens prognosis (81). However, in APS patients this has yet to be established. For instance, PHT was not reported as a major cause of death in the large cohort of 1,000 APS patients followed for 10 years, where only 22 patients had PHT (n = 22) in this cohort and hence no significant conclusions can be drawn (11). Over time, right ventricular dilation, isolated tricuspid valve regurgitation, and right heart failure may lead to secondary PHT. Different pathogenetic mechanisms, such as recurrent embolism from the veins of the lower limbs (82), in situ thrombosis, embolization from the right cardiac chambers (83), and immune mediated damage of the pulmonary vasculature leading to endothelin-1 related vascular remodeling (84) can lead to the development of CTEPH. A European multi-center study evaluated 114 patients with APS using echocardiographic studies, and found the prevalence of PHT to be 3.5% in PAPS and 1.8% in SAPS (85). In a cohort of 53 APS patients, including primary and SLE-APS, three PAPS patients (5.7%) were diagnosed with PHT at baseline TTE (86). In another cohort of 70 patients with PAPS, two were diagnosed with PHT (3%); in one patient the PHT developed following recurrent PE, whereas the second patient did not show any sign of thromboembolic disease (87). Another work analyzed the echocardiographic characteristics of 29 PAPS patients using TEE, and found five patients to have PHT (17%) (88). This high prevalence of PHT is probably related to the high frequencies of HVD (76%) and PE (31%) observed in this series, which are associated to an increased risk of PHT (89). There has been an increased interest in regard to the pathogenesis of CTEPH in the last 2 decades with a few studies describing an association between aPL and CTEPH. A retrospective analysis of 24 patients with CTEPH found that in 75% of patients, at least one thrombophilic risk factor could be identified, with the most common being aPL in 50% of cases (90). LAC and/or elevated titers of aCL were the most common abnormalities in this study. Conversely, thrombotic risk factors included elevated titers of aPL in patients with primary PHT and CTEPH, 10% of the patients with primary PHT and 20% with CTEPH (91). A study of a series of 54 patients with PHT (primary, secondary or CTEPH) confirmed, applying multivariate analysis, that elevated titers of LAC or IgG aCL were independent risk factors for the development of CTEPH (92). These findings support the need for routine screening for thrombophilia and aPL profile assessment in patients with CTEPH.

Intra-cardiac thrombus is a rare but potentially life- threatening manifestation of APS. In a cohort of 53 primary and secondary APS patients, intra-cardiac thrombus was evident in only one patient with PAPS. The overall prevalence of intra-cardiac thrombi was 1.8% in this series, though not different from controls (P = 0.4) (26). One report described a left ventricular thrombus in a 38 year old SLE-APS female patient with elevated levels of aCL IgG and IgM antibodies who presented with fever and confusion. ECHO revealed a large mobile apical thrombus, normal valves, and decreased left ventricular systolic function. Despite anticoagulation, the patient subsequently underwent a massive stroke and the thrombus was no longer present on a repeat ECHO study (13). Some reports describe thrombi appearing in all four cardiac chambers. An unusual case report described a 39-year-old male who presented with dyspnea and fever. TEE demonstrated three intra-cardiac masses. The diagnosis of APS was confirmed by an aCL assay. Despite anticoagulation therapy, the patient died 2 weeks after surgical resection. An autopsy revealed intra-cardiac thrombi in all four chambers (93). Another report described a 57-year-old woman, who was admitted for progressive dyspnea. TTE revealed a mural thrombus attached to the apex of a normally contracting LV. Cardiac magnetic resonance (CMR) examination was characteristic of ischemic injury, with no obvious LV WMA. Hence, the diagnosis of PAPS was confirmed. The authors concluded that thrombotic cardiac microvasculopathy caused myocardial ischemia which triggered clot formation (94). However, mural thrombosis in a normally contracting LV remains unusual. This case demonstrates the subtle interplay of microvascular and intra-cardiac thrombotic phenomena in APS. Severe myocardial dysfunction itself can be a risk for the formation of a left ventricular thrombus. However, findings of primary intra-cardiac thrombosis in other cardiac chambers suggest a possible role of aPL in this process. High levels of aCL IgG were found to be related to intra-cardiac thrombus formation (P = 0.007) (6). CMR is recommended for the assessment of intra-cardiac masses (95).

Most clinicians do not routinely screen APS patients for involvement of cardiac valves unless the patient is symptomatic or a new murmur is appreciated on physical examination. In APS patients, who also exhibit previous thrombosis, mainly in cases of arterial involvement, a TEE is recommended (14). In this context, it is worth noting that other clinicians recommend performing an echocardiographic study using TTE in every APS patient as an initial evaluation (95).

In a 2003 consensus report on cardiac disease in APS, the following recommendations for treating aPL-associated HVD were set (96):

1) Prophylactic low-dose aspirin alone is advised for asymptomatic patients without previous thrombosis and with no echocardiographic evidence of valvular vegetation or dysfunction.

There are conflicting data regarding the effect of antiplatelet agents and warfarin on regression of the valvular lesions, but these treatments may prevent embolic events (92). Some studies found no benefit in regard to regression of valvular vegetations with antiplatelet and/or anticoagulant therapy in PAPS patients (29, 97). In addition to anticoagulation therapy, some experts may add other treatments, such as low-dose aspirin, statins, and hydroxychloroquine (HCQ) (98). A recently published case report described a PAPS patient receiving longterm rivaroxaban who was diagnosed with asymptomatic NBTE. Upon confirmation of diagnosis, the patient was treated with HCQ and corticosteroids (CS) in addition to low-molecular-weight heparin (LMWH). Under this treatment regimen the size of the vegetation decreased by half at 1 week and completely resolved at 6 months (99). Substantial data is lacking on the efficacy of CS in individuals with aPL-associated HVD and remains controversial (100). However, the decline in prevalence of NBTE lesions at autopsies following the introduction of CS, supports their possible beneficial effect (101). One protocol recommends a 1 month course of high dose CS with follow-up echocardiograms in order to determine the appropriate rate of CS taper, along with anticoagulation to prevent embolic stroke (102). CS may expedite healing of vegetations, preventing scarring and eventually valve dysfunction (22). The task force report published in 2011 (14) provided no recommendations for treating valvular lesions.

Surgical consultation may also be necessary in selected cases of aPL-associated HVD with severe valvular dysfunction and recurrent embolism despite anticoagulation. An increased risk for morbidity and mortality in APS patients following valve-replacement surgery is well-documented. Most complications were due to bleeding and thrombosis (103). In a retrospective analysis of 32 APS patients, who underwent valve replacements, mortality rates were 12.5%, while 50% of patients had an uneventful outcome (104). In other studies, even higher mortality rates (>20%) after valve-replacement surgery were reported (105–107). The type of valve for replacement, whether mechanical or biologic is yet to be established. Biologic valves have a theoretical advantage of less thromboembolic events compared with mechanical prostheses (105). On the other hand, given that these patients are usually young and commonly require anticoagulation for previous thromboembolism, other studies recommend the use of mechanical valves (106). Moreover, some risk might exist for immunologic deterioration of tissue heart valves. One study found no differences in outcome between types of valves utilized (104). More studies are necessary in order to conclude which type of prosthetic valve would be better in this setting, and long-term results are lacking. Heart valve replacement poses significant challenges on the management of APS patients who require this surgery, especially during the perioperative period. Assessing thrombotic and hemorrhagic risks as well as careful monitoring are mandatory procedures to avoid complications. The use of relatively new valve surgery techniques, such as trans-catheter aortic-valve replacement (TAVR), may represent a safer approach for patients with APS. However, longterm results are not available and additional studies are required in order to assess the outcome in this group of patients.

Prophylactic antibiotic therapy for the prevention of developing infective endocarditis in patients with primary or secondary APS and valve lesions is not warranted (108).

There are no substantial additions to therapeutic considerations for APS patients with CAD. However, aggressive monitoring of traditional risk factors should be performed for lifestyle modification and pharmacological treatment. For CAD, Aspirin prophylaxis was not proven to be an added benefit over warfarin therapy alone (58). Pharmacological therapies include anti-platelets, anticoagulants, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and statin therapy. Statins have a beneficial effect in various mechanisms in addition to their effect on lipid profile, including their ability to enhance the stability of atherosclerotic plaques, improve the endothelial function (109, 110), decrease oxidative stress (111) and suppress the inflammatory responses (112). All of these mechanisms may contribute to thrombosis prevention in APS patients. HCQ has been reported to exert anti-atherogenic properties. However, recommendations for HCQ use are reported in addition to therapeutic anticoagulation for secondary prevention of arterial thrombotic events in PAPS (57, 113). Therapy with CS in APS-associated ischemic heart disease may be detremental (58). Anticoagulation is optimal with a target INR range of 2.0–3.0 as long term therapy (114, 115), and with escalation to a higher target INR should thrombosis recur (116). Ideally, young APS patients who present with STEMI should undergo primary percutaneous coronary intervention (PCI) (117) and thrombus aspiration in selected cases. In APS patients undergoing PCI a careful balancing between the risk of bleeding and that of thrombosis should be executed. Stenting should be weighed carefully, and kept available for patients with underlying coronary atherosclerosis in the culprit lesion (118). Dual antiplatelet therapy is usually given as short term treatment in ACS with stent implantation. Thrombolysis in hypercoagulable states has also been described in the literature and may be the appropriate treatment for selected APS patients presenting with MI (119). Coronary artery bypass grafting (CABG) is indicated in some APS patients with CAD, and efforts should be directed at assuring adequate perioperative anticoagulation to avoid complications.

Current guidelines should be implemented in standard medical therapy for systolic heart failure, including ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and ARNI (angiotensin receptor-neprilysin inhibitor). In addition to these agents, APS patients with myocardial dysfunction require long-term anticoagulant therapy to minimize the possibility for thromboembolism of large vessels and lower the risk of thrombotic microangiopathy, which might lead to subsequent cardiac complications. In patients with definite APS and in the absence of contraindications, warfarin is the treatment of choice, with a target INR of 2.0–3.0 while the target INR depends on the causes of the myocardial dysfunction and individual's risk (113). Patient with symptomatic heart failure and reduced ejection fraction despite optimal pharmacological therapy necessitate evaluation for cardiac resynchronization therapy (CRT), left ventricular assist device (LVAD) and heart transplant. These interventions are at a very high risk of failure in APS patients, due to the thrombotic burden of the disease that damages even the device or transplanted heart, and the possible nephrotoxicity of immunosuppressive therapy (120). Nevertheless, there is no consensus on how to manage the myocardial dysfunction in APS (96); it is unclear whether antiplatelet, anticoagulant or other therapies may prevent the associated diastolic dysfunction or dilated cardiomyopathy (18).

The mainstay of treating PE and CTEPH in APS patients is life-long anticoagulant therapy. Patients with progressive CTEPH should be evaluated by a multidisciplinary team of experts. Surgical pulmonary thromboendarterectomy should be performed to prevent irreversible damage, improve hemodynamics, exercise capacity and survival (58, 121, 122). In symptomatic patients with CTEPH who are ineligible for surgery, or when irreversible pulmonary resistance is already evident, off-label use of drugs approved for pulmonary arterial hypertension, such as prostacyclins and endothelin receptor antagonists, should be considered. A phase 3 randomized trial compared a group of 173 patients treated with riociguat (a soluble guanylate cyclase stimulator) to a group of 88 individuals who were administered a placebo. The results showed that riociguat significantly improved the clinical outcomes in patients with CTEPH who were ineligible for surgery or who had persistent/recurrent PHT after undergoing pulmonary endarterectomy (122). Since inflammatory mechanisms may contribute to APS-associated CTEPH pathogenesis, the addition of immunosuppressive therapy may be beneficial.

Adequate maintenance anticoagulation therapy (target INR 3.0–4.0) is needed in APS patients with intra-cardiac thrombi. The role of surgical intervention remains controversial. To prevent the recurrent intra-cardiac thrombotic events, the thrombus should be surgically removed as early as possible and adequate maintenance anticoagulation therapy should be provided. The 2003 expert committee recommended treatment with warfarin anticoagulation along with cardiac surgeon consultation (96). To date, there are no randomized trials comparing different treatment strategies for this rare complication of APS.

The management of APS has been in continuous evolution over the past three decades. Nevertheless, antiplatelet and anticoagulant agents are still the cornerstone of APS treatment. As we discussed in detail, anticoagulation (mainly warfarin or heparin) is also the mainstay of therapy in the various cardiac complications associated with APS. The role of direct oral anticoagulants (DOACs) in managing thrombotic APS manifestations is still unclear and there is insufficient evidence to establish recommendations regarding their use in these patients (123). The current trend aims at providing individually tailored treatment strategies, according to each patient's risk stratification (124).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.