Acute dilated cardiomyopathy in the setting of catastrophic antiphospholipid syndrome and thrombotic microangiopathy: A case series and review

Abstract Catastrophic antiphospholipid antibody syndrome (CAPS) is a rare form of antiphospholipid syndrome, an autoimmune condition characterized by vascular thromboses, pregnancy loss, and antiphospholipid (aPL) antibodies. Diagnosis of CAPS relies on thrombosis of at least three different organs systems over 1 week, histopathological evidence of small vessel occlusion, and high aPL antibody titers. In a subset of precipitating circumstances, activation or disruption of endothelial cells in the microvasculature may occur along with cardiomyopathy. We present two cases of CAPS‐associated dilated cardiomyopathy at our institution, focusing on disease management, pathophysiology, and treatment. These patients were of Southeastern Asian descent, raising the possibility of genetic polymorphisms contributing to the development of cardiomyopathy. Both met CAPS criteria and both demonstrated clinicopathologic thrombotic microangiopathy (TMA) and complement activation and developed severe dilated cardiomyopathy with shock. Complement activation plays an important role in the development of CAPS and may be important in the pathogenesis of CAPS‐associated cardiomyopathy. Clinical suspicion for TMA as a pathophysiologic mechanism of unexplained heart failure in CAPS is important and increased awareness of cardiac side effects is necessary so that early treatment can be initiated to halt further cardiac and systemic complications.

circumstances such as infection [5,6], neoplasm [7], anticoagulation withdrawal [8], and pregnancy [9,10]. Although diagnosis can be clinically challenging, international consensus criteria exist specifying diagnosis based on thrombosis of at least three different organs systems over a period of 1 week, confirmed aPL antibodies, and histopathological evidence of multiple small vessel occlusions [11,12].
CAPS is thought to be due to the pathogenic effects of aPL on the vascular endothelium [13]. This can lead to thrombotic microangiopathy (TMA) characterized by development of fragmentation hemolytic anemia, thrombocytopenia, and organ dysfunction due to small vessel thrombosis, resulting in ischemia [14].
As a multisystem thrombophilic disorder, CAPS often manifests clinically with significant cardiac disease. In a study of 500 patients from the International CAPS Registry, 50% of patients with CAPS had a component of cardiac disease involvement [15]. In the majority of these cases, the pathologic findings showed evidence of myocardial infarction and valvular disease. In addition, Libman-Sacks endocarditis has been reported in 13% of CAPS patients with heart involvement and may be accompanied by stroke [16,17]. Cardiomyopathy is less frequently described, but may develop as a consequence of coronary artery occlusion or significant valvulopathy [18]. However, rare case reports have identified CAPS patients with dilated cardiomyopathy, normal coronary angiogram, negative viral serologic tests, and no other identifiable causes of heart failure on routine testing [19][20][21][22][23]. In this cohort of patients, endomyocardial biopsy can demonstrate clinicopathologic features of TMA. This subset is especially noteworthy because of the difficulty in diagnosis, unique pathophysiologic mechanisms at play, and potential reversibility of underlying myocardial injury with therapy directed at suppressing overactivation of the complement system [24][25][26]. We present two cases of CAPS at our institution in whom diffuse cardiomyopathy with evidence of TMA was identified.
The relevant literature is reviewed, and the role of complement inhibition in the treatment of certain subtypes of cardiomyopathy due to TMA is discussed.

DISCUSSION
CAPS is a severe and rare complication of APLS with multiorgan thrombosis frequently involving the kidneys, lungs, brain, and heart [27,28].
Here, we described two patients treated at our institution with CAPS and clinicopathologic signs of TMA who developed severe dilated car- The incidence of cardiomyopathy in association with TMA is not well studied. In a retrospective study of 220 adult patients diagnosed with TMA at the Mayo Clinic, the estimated incidence of heart failure, defined by strict Framingham criteria, was roughly 10% and was associated with increased mortality [29]. The etiology of heart failure, however, was not specified. In a study of 17 autopsied patients with TTP, 13 had evidence of extensive small-vessel thromboses within the heart arterioles [30]. Case reports also describe cardiomyopathy associated with TTP in CAPS, with two of three specifically showing improvement with treatment of the underlying disease, including plasmapheresis [31][32][33]. Likewise, in Shiga toxin-producing Escherichia coli-associated HUS, there have been described cases of dilated cardiomyopathy occurring in children and adults, with favorable cardiac outcomes after treatment [34,35]. Furthermore, patients with cardiomyopathy secondary to complement-mediated TMA, including those with atypical HUS and those with known complement Factor H gene mutations or autoantibodies directed against Factor H, showed clinical response to eculizumab treatment with improvement in their cardiomyopathy [36]. Cases of cardiomyopathy and complement-mediated TMA are additionally described in the setting of preeclampsiainduced premature delivery [9,10,37] and in diverse settings in the pediatric population [38,39] with improvement with eculizumab [40]. Interestingly, Takotsubo cardiomyopathy has been described atypical HUS as well [41].
The role of CAPS-related TMA and cardiomyopathy has not been frequently reported. In a single-institution series of 14 patients with CAPS, one patient was reported to have cardiomyopathy associated with the syndrome, which was confirmed with endomyocardial histology showing small vessels with endoluminal thrombosis and perivascular/intramural inflammatory cells [42]. Although uncommon, there have been other reported cases of cardiomyopathy suspected due to CAPS-induced TMA [43][44][45].
The mechanism of CAPS-precipitated TMA and associated cardiomyopathy is thought to be an effect of aPL antibodies on endothelium integrity [46][47][48]. The large-scale thrombosis occurs partly through a cytokine storm, propagated by an immune response to peptide sequences with structural homology to aPL antibodies, with subsequent increase in complement activation resulting in the release of proinflammatory and prothrombotic cytokines that disrupt endothelial cell membranes and activate toll-like receptors [6,49,[55][56][57]. Thrombosis then leads to secondary consumption of protein C and antithrombin and an increase in plasminogen activator inhibitor type-1 feeding a pro-coagulant cycle. In addition, activation of platelets and increased expression of tissue factor further accelerates clot formation [13,50].
Thrombin itself can enzymatically cleave C5 to C5a, inducing more cytokine activation as well as activation of more terminal complement through more C5b generation.
Recent studies also suggest evidence of complement activation in the thrombotic small vessels of patients with CAPS, possibly triggered by immune complex deposition of aPL antibodies. In vivo preclinical data suggest that in C3 or C5-deficient mice, the effect of aPL antibody-mediated thrombosis is attenuated in the same way as with a C5 inhibitor in wild-type mice, suggesting that complement may be activated in patients with aPL antibodies resulting in excessive generation of C5a (which induces neutrophil and monocyte tissue factordependent procoagulant activity as well as platelet aggregation and activation) [51]. This has ushered in a new treatment paradigm of TMAassociated cardiomyopathy with C5 inhibitor eculizumab in addition to traditional use of anticoagulation, corticosteroids, plasma exchange, and IVIG [52][53][54].
Going forward, it is critically important to better understand the microvascular physiology and the role of complement in cardiomyopathy associated with CAPS TMA. Future registry participation and detailed mechanistic insight is needed to clarify this problem in rare diseases such as CAPS. One should have a high clinical suspicion for TMA as a pathophysiologic mechanism of unexplained heart failure in CAPS.
Increased awareness about the potential cardiac effects in CAPS is necessary so that early treatment can be initiated in order to halt further cardiac and systemic complications.

AUTHOR CONTRIBUTIONS
All authors helped with critical writing; conceptualized and designed the study; analyzed and interpreted the data; revised the intellectual content; and gave final approval for the version to be published.