Maurizio Acampa

Arrhythmic risk in rheumatoid arthritis: the driving role of systemic inflammation

When compared to the general population, patients with rheumatoid arthritis (RA) have an overall standard mortality ratio of approximately two, with more than 50% of premature deaths attributable to cardiovascular disease (CVD). Moreover, RA patients were twice as likely to experience sudden cardiac death (SCD) compared with non-RA subjects, as a putative consequence of an increased incidence of malignant arrhythmias. Accordingly, mounting data indicate that in patients affected with RA the risk of developing rhythm disturbances, particularly tachyarrhythmias, is high. Although a number of papers reviewing the problem of cardiovascular involvement in RA are currently available, the main focus is on the mechanisms of accelerated atherosclerosis and related ischemic consequences in the clinical setting. On the contrary, only little consideration has been specifically given to the arrhythmic risk so far. In the light of this concern, in the present paper we reviewed the topic with the aim to put together the apparently fragmentary existing information, with particular attention to the putative role of chronic systemic inflammation characterizing the disease. In fact, although the underlying mechanisms accounting the arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by inflammatory activation, able to promote arrhythmias either indirectly, by accelerating the development of structural CVD, and directly by affecting cardiac electrophysiology. In this view, lowering inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk and prevent life-threatening complications in these patients.

Autoantibody-mediated cardiac arrhythmias: mechanisms and clinical implications

Cardiac arrhythmias, including conduction defects and tach- yarrhythmias, represent an important source of morbidity and mortality in industrialized countries. Among the different pathophysiological mechanisms involved in the arrhythmogenesis, an inappropriate activation of the immune system represents a field of recent increasing interest. In fact, a large amount of studies suggest that specific autoantibody may be significantly involved in the pathogenesis of cardiac arrhythmias not only in the course of systemic autoimmune disease, but also in a number of rhythm disorders currently classified as “idiopathic.” Although the strongest evidence concerns the relationship between anti-Ro/SSA antibodies and the development of congenital heart block in foetus and newborn, other specific autoantibodies demonstrated the aptitude to affect directly the myocardial tissue, thus producing interference in its bioelectric activity thereby leading to rhythm disorders, also life-threatening. The identification of an immunological autoantibody-mediated mechanism opens new perspectives in the treatment and prevention of cardiac arrhythmias in such patients, including the use of immunosuppressive agents and/or the removal of autoantibodies by immuno-adsorption technique.

Progressive Cardiac Dysautonomia Observed in Patients Affected by Classic Rett Syndrome and Not in the Preserved Speech Variant

Incidence of sudden death in Rett syndrome is greater than that of the general population, and cardiac electrical instability is a prime suspect cause. The objective of the present study was the evaluation of heart rate variability, a marker of autonomic activity, in females affected by classic Rett syndrome and atypical variants for a possible explanation of the higher risk for sudden death observed in these subjects. Our study showed that girls with classic Rett syndrome had significantly lower heart rate variability and longer corrected QT intervals than in atypical Rett syndrome and age-matched healthy girls. Reduction of heart rate variability progresses with age and with the clinical stage of the syndrome. These results suggest the possible role of the progressive cardiac dysfunction in the sudden death associated with Rett syndrome. (J Child Neurol 2001;16:370-373).

Time Course of Corticospinal Excitability and Autonomic Function Interplay during and Following Monopolar tDCS.

While polarity-specific after-effects of monopolar transcranial direct current stimulation (tDCS) on corticospinal excitability are well-documented, modulation of vital parameters due to current spread through the brainstem is still a matter of debate, raising potential concerns about its use through the general public, as well as for neurorehabilitation purposes. We monitored online and after-effects of monopolar tDCS (primary motor cortex) in 10 healthy subjects by adopting a neuronavigated transcranial magnetic stimulation (TMS)/tDCS combined protocol. Motor evoked potentials (MEPs) together with vital parameters [e.g., blood pressure, heart-rate variability (HRV), and sympathovagal balance] were recorded and monitored before, during, and after anodal, cathodal, or sham tDCS. Ten MEPs, every 2.5-min time windows, were recorded from the right first dorsal interosseous (FDI), while 5-min epochs were used to record vital parameters. The protocol included 15 min of pre-tDCS and of online tDCS (anodal, cathodal, or sham). After-effects were recorded for 30 min. We showed a polarity-independent stabilization of cortical excitability level, a polarity-specific after-effect for cathodal and anodal stimulation, and an absence of persistent excitability changes during online stimulation. No significant effects on vital parameters emerged both during and after tDCS, while a linear increase in systolic/diastolic blood pressure and HRV was observed during each tDCS condition, as a possible unspecific response to experimental demands. Taken together, current findings provide new insights on the safety of monopolar tDCS, promoting its application both in research and clinical settings.

Association between high sensitivity C-reactive protein, heart rate variability and corrected QT interval in patients with chronic inflammatory arthritis

BACKGROUND The risk of sudden cardiac death is increased in chronic inflammatory arthritis, particularly rheumatoid arthritis (RA). To evaluate the putative effect of systemic inflammation on heart rate variability (HRV) and ventricular repolarization in chronic inflammatory arthritis, we analyzed in these patients the possible relationship among HRV parameters, QT interval, and high sensitivity C-reactive protein (hsCRP). METHODS One hundred-one patients with chronic inflammatory arthritis underwent a 15-minute ambulatory twelve-channel electrocardiogram-recording, to evaluate HRV and QT interval, as well as a venous withdrawal for hsCRP as an estimation of ongoing systemic inflammation. RESULTS In patients with chronic inflammatory arthritis, hsCRP is inversely correlated with HRV and directly with QTc duration, but while hsCRP is associated with HRV independently from any other investigated factor, the association between hsCRP and QTc seems to be an indirect consequence of the autonomic dysfunction itself. Within the whole cohort of patients, those subjects having elevated hsCRP levels displayed both a significant reduction in HRV and a prolongation of QTc with respect to patients with a normal hsCRP value. A similar, although less marked, degree of HRV depression and QTc prolongation was found in RA patients when compared to subjects with spondyloarthritis (SpA) and healthy controls. CONCLUSIONS These data provide evidence of a link between systemic inflammation and the arrhythmic risk in patients with chronic inflammatory arthritis, also putatively explaining, at least in part, how the different inflammatory load characterizing RA and SpA parallels the different risks of cardiovascular death in these two conditions.

Anti-Ro/SSA-Associated Corrected QT Interval Prolongation in Adults: The Role of Antibody Level and Specificity

Recent evidence suggests that anti‐Ro/SSA antibodies, strongly associated with the development of congenital heart block, may also be arrhythmogenic for the adult heart. In fact, anti‐Ro/SSA–positive patients with connective tissue disease (CTD) frequently display corrected QT (QTc) prolongation associated with an increase in ventricular arrhythmias. However, QTc prolongation prevalence markedly differs throughout the studies (10–60%), but the reason why is not yet clear. The aim of this study was to evaluate whether anti‐Ro/SSA–associated QTc prolongation in adult patients with CTD is related to antibody level and specificity.

Sympathetic overactivity and plasma leptin levels in Rett syndrome

Rett syndrome (RTT) is a severe developmental-neurological disorder, characterized by profound and progressive loss of intellectual functioning, occurring after a period (of at least 6 months) of normal development with classic stereotype hand movements, gait ataxia, jerky truncal ataxia, deceleration of brain and body organ growth and cardiac dysautonomia. Pathogenesis of sympathetic overactivity in RTT is unknown, but a previous study observed increased plasma leptin levels in Rett girls and it is well known the role of leptin in the regulation of sympathetic nervous system activity. Aim of our study is to evaluate a relationship between plasma leptin levels and sympathetic activity in RTT. Thirty-two female patients (12.1+/-6.3 years), affected by RTT were enrolled in the study. In all the subjects, we analyzed heart rate variability, QT corrected interval and plasma leptin levels. A significant correlation was found between plasma leptin levels and LF/HF (expression of sympatho-vagal balance) (Spearman r=0.44, p=0.001). There is also a significant negative correlation between HF component (expression of vagal activity) and plasma leptin levels (Spearman r=-0.037, p=0.03) and a positive correlation between LF component and plasma leptin levels (Spearman r=0.047, p=0.01). These results show that in RTT higher plasma leptin levels appear to be associated with sympathetic overactivity, suggesting a role for leptin in cardiac dysautonomia.

Effects of Acetyl-L-carnitine on Cardiac Dysautonomia in Rett Syndrome: Prevention of Sudden Death?

There is a higher incidence of sudden death in patients with Rett syndrome than individuals in the general population. Previous studies have implicated cardiac dysautonomia and a long QT interval as causative factors. Because carnitine plays a critical role in cellular metabolism and may have beneficial effects on cardiac and nerve function, we investigated the effects of long-term treatment with acetyl-L-carnitine on heart rate variability and electrocardiographic abnormalities in 10 girls with Rett syndrome and compared the results with 12 control patients (girls with Rett syndrome who were not treated). The age range of the subjects was 2–21 years. The study design called for the evaluation of heart rate variability, corrected QT interval, and QTc dispersion. In the 10 Rett girls treated with acetyl-L-carnitine, a significant increase in heart rate variability was observed. To explain these results, we hypothesize that acetyl-L-carnitine has a neurotrophic action on the cardiac autonomic nervous system. This effect may reduce the risk of sudden death in patients with this syndrome.

Arrhythmogenic effects of anti-Ro/SSA antibodies on the adult heart: More than expected?

The arrhythmogenicity of anti-Ro/SSA antibodies for the foetal heart and their crucial role in the development of congenital heart block is now well established, representing a paradigmatic model of passively acquired autoimmunity. Recently, intriguing data suggest that also the adult heart may represent a possible target of anti-Ro/SSA antibody-mediated autoimmune injury. The prolongation of the QTc interval, possibly resulting from a direct inhibitory interaction between the anti-Ro/SSA antibodies and the potassium current I(Kr) in the heart seems the abnormality more frequently observed in adults with anti-Ro/SSA-positive CTD. Although the possibility that anti-Ro/SSA positivity may be considered a risk factor for arrhythmic sudden death in adults has not been demonstrated as yet, preliminary data suggest a relationship among anti-Ro/SSA antibodies, QTc prolongation, and the prevalence of ventricular arrhythmias, also life threatening, in adult patients.

Antiarrhythmic Potential of Anticytokine Therapy in Rheumatoid Arthritis: Tocilizumab Reduces Corrected QT Interval by Controlling Systemic Inflammation

Patients with rheumatoid arthritis (RA) are twice as likely to experience sudden cardiac death compared with individuals without RA. Although the underlying mechanisms of this have not been clarified, evidence points to the effects of systemic inflammation on ventricular repolarization. Accordingly, prolongation of the corrected QT (QTc) interval is more frequent in patients with RA compared with individuals without RA also correlating with C‐reactive protein (CRP) and predicting all‐cause mortality. Tocilizumab (TCZ) is an anti–interleukin‐6 receptor antibody that potently inhibits inflammatory activation in RA, with rapid normalization of acute‐phase reactant levels, including the CRP level. Therefore, we hypothesized that TCZ may normalize the QTc interval by dampening systemic inflammation, thus reducing the risk of arrhythmia in patients with RA.