UCTD was diagnosed as defined by Raynaud's phenomenon with swollen hands and highly positive anti-RNP antibody titer, associated with autoimmune conditions including hypergammaglobulinemia, reactive lymphadenopathy, Coombs'-positive anemia, and APS-2. The patient had cardiovascular autonomic dysfunction as evidenced by symptomatic orthostatic hypotension in the absence of volume depletion as well as significantly reduced heart variability on ambulatory electrocardiography. Following development of complete heart block, electrophysiological studies and eventual pacemaker insertion were not performed because of severe neurological disability and poor prognosis.
Cardiac arrhythmias have been described in autoimmune diseases with antibodies causing inflammatory myopathies [7
]. In the current patient, anti-SSA/Ro antibodies may well have contributed to the development of sudden cardiac arrest. A high titer of anti-RNP antibodies in patients with UCTD is a powerful predictor of later evolution into mixed (M)CTD [8
], for which anti-Ro/SSA-mediated non-fatal complete heart block has been reported as rare event [1
]. The patient reported here did not yet fulfil diagnostic criteria for MCTD. As she was positive for both anti-RNP and anti-SSA, however, the presence of anti-RNP antibodies could be predictive of later development of MCTD.
Signs of an autonomic nervous system dysfunction involving the cardiovascular system can be discerned in the majority of anti-SSA/Ro- and anti-SSB/La-positive patients with CTD [3
]; on this basis, a putative role for cardiovascular autonomic dysfunction in favoring an adverse outcome of complete heart block by impairment of compensatory shock mechanisms as was seen in the present patient, cannot be ruled out. Moreover, it should be underlined that cardiovascular autonomic dysfunction was similarly detected in anti-SSA/Ro-negative CTD patients [3
], as it is present in other autoimmune diseases as well [9
], thus suggesting that it is a feature characteristic of the disease independently of the presence of such autoantibodies.
Hypothyroidism at the moment of the cardiac arrest may be a feature of peculiar pathogenetic relevance. In fact, in patients with hypothyroidism (also subclinical), severe atrioventricular block of different degrees disappeared after supplementation with thyroxine [10
]. Moreover, Spence et al. [12
] demonstrated that maternal hypothyroidism increased markedly the risk (about 9-fold) of delivering a child with complete congenital heart block in women with circulating anti-SSA/Ro antibodies. Finally, Baumgart et al. [13
] described the case of a complete heart block developing in a woman affected by anti-60 kD SSA/Ro-positive Sjögren's syndrome with concomitant hypothyroidism and hypoadrenalism secondary to hypopituitarism. The patient, early implanted with a VVI pacemaker, was then treated with a substitution regimen with prednisolone and thyroxine resulting in the restoration of the sinus rhythm. On the basis of these data, in accordance with a very recent review on this topic [1
], it is possible to hypothesize that the conduction system of adult heart may display, rather than an absolute resistance, a different degree of vulnerability to anti-SSA/Ro antibodies with respect to fetal heart.
Two fundamental pathophysiological mechanisms have been proposed to account for autoantibody-mediated arrhythmogenic effects: (a) a direct mechanism, in which cardiomyocytes, and their electrophysiological properties, constitute the primary target of the autoantibodies; (b) an indirect mechanism, in which the autoantibody-mediated immune response involves the cardiac electrophysiology only secondarily [14
]. The latter is the case of anti-cardiomyocyte autoantibodies producing a myocardial damage leading to the development of dilated cardiomyopathy and heart failure, which eventually represent the major cause of severe ventricular arrhythmias), or autoantibodies targeting structures indispensable for the myocardial homeostasis such as nerves and vasculature (references in [14
]). Given the absence of both clinical and objective findings suggesting dilated cardiomyopathy in the case presented here, a direct mechanism most likely accounted for bradycardia.
In the context of predisposition, additional concomitant factors (such as hypothyroidism) may be able to precipitate the onset of severe heart block. The patient of the present case report was not in a hypothyroid state at the moment of heart block development as fT4 levels were normal because sufficiently substituted with thyroxine. TSH was slightly elevated and fT3 was low which is compatible with euthyroid sick syndrome [15
Differential diagnoses of bradycardia and complete heart block have to be reasonably ruled out. The patient presented here did not assume medications potentially affecting the conduction tissue; clinical, laboratory and ECG data suggesting structural heart disease were normal, making underlying myocarditis and acute myocardial infarction unlikely, putatively resulting from coronary vasculitis or accelerated atherosclerosis, nor were echocardiographic signs of cardiac amyloidosis present in consideration of the concomitant cardiovascular autonomic dysfunction evident.
The fact that a post-mortem examination has not been performed in the patient is a clear limitation of the study.