Severe spongiform aortic stenosis in monozygotic twins with anti-phospholipid syndrome related to systemic lupus erythematosus

S. Chandar, S. Riminton1, J. Yiannikas and L. Kritharides

Departments of Cardiology and
1 Immunology, Concord Repatriation General Hospital, University of Sydney, Australia

SIR, Monozygotic twin concordance rate for systemic lupus erythematosus (SLE) is 24–57% with an overall population prevalence of 0.2% suggesting a dominant role of genetic predisposition to SLE susceptibility [1]. Genetic contribution to the incidence of SLE needs to be distinguished from that to the individual target organ injury within the disease. In a mouse model, the Sle 3 allele was necessary for renal manifestations of the disease [2]. Few familial associations of the anti-phospholipid syndrome (APS) have been described in detail [3, 4], and twin studies provide an important opportunity to evaluate genetic factors in specific disease manifestations. We report a novel form of severe spongiform aortic stenosis in identical twin sisters with SLE-related APS; their mother is SLE negative for anti-phospholipid antibodies (aPL) and has normal heart valves.

Twin A, a 48-yr-old woman with histologically confirmed lupus nephritis (biopsy showing diffuse proliferative glomerulonephritis with positive mesangial immunostaining for IgG, IgA, IgM, C3 and C1q), presented with severe heart failure. Other disease manifestations included arthropathy, rash, Raynaud's phenomenon, cerebrovascular disease, pulmonary veno-occlusive disease, livedo reticularis and recurrent fetal loss. Clinically, she demonstrated severe aortic stenosis (AS). There were no signs of infective endocarditis, including negative blood cultures. Transthoracic echocardiographic examination (TTE) confirmed the severe AS (peak gradient 70 mmHg) with unusual proliferative thickening on the anterior leaflet consistent with, but atypical of, vegetation. Pulmonary hypertension was documented on two different TTEs, the maximal estimated pressure being 50 mmHg. At elective aortic valve replacement (AVR), the valve was reported as markedly thickened, stenotic and bicuspid. The histology showed fibrosis and calcification with no evidence of vegetations or thrombosis. Immunohistochemical staining was negative for IgG, IgA and IgM. See Table 1Go for serology. She succumbed to non-cardiac multisystem manifestations of the disease 4 yr after AVR.


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TABLE 1. Blood results

 
Twin B, the 49-yr-old monozygotic twin of twin A with prior history of SLE-related rash, arthralgia and fetal loss, presented with exertional symptoms and systolic murmur of aortic stenosis. The only abnormality on TTE was unusual proliferative thickening of both aortic leaflets with peak gradient of 86 mmHg. At AVR, the valve was described as bicuspid, spongy, irregularly thickened and markedly distorted. The histology revealed fibrosis and calcification with no evidence of vegetations, thrombosis or detectable immune deposits on the valve. See Table 1Go for serology. She remains well, apart from minor effort dyspnoea.

The 80-yr-old mother of the above twins has established serological features of SLE, mild fibrotic lung disease and sicca complex. Anti-cardiolipin antibody (aCL) was not detected; TTE was normal. There is no information available on the twins' father who, apparently, died at age 51 of Bright's disease.

Aortic valve involvement in the APS is rare, and stenosis exceptional. Aortic stenosis was seen in <1% of patients with APS [5], therefore the probability of this occurring in twins by chance alone is <1:10 000. Studies suggest that there may be a link between aPL and heart valve pathology. In patients with SLE, valvulopathy is more common in the presence of aPL than in their absence [5, 6].

This is the first report of severe aortic stenosis in identical twins with SLE-related APS. The unusual proliferative, spongy macroscopic appearance of their valves is inconsistent with pure bicuspid aortic stenosis that typically demonstrates severe nodular calcification [7]. Furthermore, there were no vegetative lesions typical of SLE or thrombotic lesions typical of APS. It is unlikely that steroids contributed to the histopathology. Only twin A had taken steroids, despite very similar fibrosis in both; in addition, the fibrous scarring related to steroid treatment of Libman–Sacks valvulopathy most commonly leads to valvular regurgitation rather than stenosis [8]. This suggests a novel pathophysiology, possibly arising from the combination of the presence of aCL and haemodynamic turbulence due to congenitally bicuspid valves. That very similar valve pathology occurred in both twins at roughly the same age strongly supports a genetic contribution.

The major histocompatibility complex (MHC) is the most frequently implicated genetic factor in autoimmune disease [9]. Certain HLA class II associations with the APS including HLA-DR4 and DR7, with DRw53 and DQw7 (DQ B1 0301) being implicated as contributors of aPL production, have been described [3, 4, 10]. The mother (aCL-negative and no valvulopathy) and the living twin (strong aCL positivity and severe aortic stenosis) share DQ B1 0301, suggesting that the pathological contribution of this allele was insufficient in the mother to produce the target organ damage.

We hypothesize that the circulating aPL interact with the underlying structural and haemodynamic changes of the bicuspid aortic valve to produce an unusual spongy, proliferative thickening of the valve. In these patients, genetic susceptibility loci appear to contribute independently to bicuspid valves, SLE and APS collaborating in the pathogenesis of a rare spongiform aortic stenosis. This is a unique example of human genes contributing to a specific target organ manifestation of SLE and APS.

Notes

Correspondence to: S. Chandar, Department of Cardiology, Level 3 Mutiblock, Concord Repatriation General Hospital, Concord, NSW 2139, Australia. E-mail: satishcha{at}hotkey.net.au Back

References

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Accepted 16 September 2002





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