The hallmark cardiac manifestation associated with autoantibodies reactive with the intracellular soluble ribonucleoprotein SSA/Ro, is complete atrioventricular block that affects fetuses and/or newborn of mothers with anti-Ro antibodies. Anti-Ro antibodies are not considered pathogenic for the adult heart conduction system but emerging new clinical evidence demonstrates that the prevalence of corrected QT (QTc) and the frequency of complex ventricular arrhythmias is alarmingly higher in patients with various autoimmune diseases. Patients with moderate to high levels (e50 U/ml) of anti-Ro antibodies exhibit longer QTc intervals and those with low antibody titers show normal QTc. The pathogenesis of this autoimmune associated long QT syndrome and the variability in QTc values in patients positive to anti-Ro antibodies is not well understood The preliminary data suggest that anti-Ro antibodies are arrhythmogenic as a result of interference with the ventricular repolarization. The K channel HERG which conducts the rapidly activating delayed K current, IKr, plays a major role in ventricular repolarization and is the main target for drugs-induced QTc prolongation. We hypothesize that anti-Ro antibodies from patients with QTc prolongation specifically target and inhibit HERG channel function, prolong action potential duration in a dose-dependent manner resulting in delayed repolarization seen as QT prolongation on the surface electrocardiogram. This hypothesis will be tested via four aims:
Aim#1 : To investigate the electrophysiological basis of variability of QTc prolongation in anti-Ro antibody positive adult patients with connective tissue disease (CTD).
Aim #2 : To investigate the electrophysiological basis for the absence of QTc prolongation in a subset of CTD adult patients with anti-Ro antibodies.
Aim#3 : To elucidate the possible antigenic target of pathological antibodies on the HERG channel.
Aim#4 : To establish animal models of autoimmune-associated QTc prolongation. Significance to Veterans Health: Patients with connective tissue diseases have a high prevalence of QTc prolongation and high incidence of life threatening arrhythmias. QTc prolongation associated with anti-Ro antibodies per se confers an increased risk of developing cardiac arrhythmias and represents an additional risk factor for patients with pre-existing acquired or congenital long QTc. A major impact from this study is the potential recommendation that patients with moderate to high anti-Ro antibodies should benefit from routine ECG testing and those identified with anti-Ro antibodies associated QTc prolongation should receive counseling, including education about drugs that may put them at risk for life threatening arrhythmias. This is relevant to Veterans health because of the highly prevalent use of antipsychotic and antidepressant drugs that are known to prolong the QTc interval in both men and women Veterans.

Public Health Relevance

The majority of sudden cardiac deaths are caused by ventricular arrhythmia associated with prolongation of QT interval (long QT syndrome). In this application, we demonstrate that anti-Ro antibodies from patients with autoimmune diseases can cause a novel long QT syndrome. These patients should benefit from ECG testing and those already identified with long QT syndrome should receive counseling about drugs that may put them at risk for life threatening arrhythmias.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002137-01A1
Application #
8635435
Study Section
Cardiovascular Studies A (CARA)
Project Start
2013-10-01
Project End
2017-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA New York Harbor Hlthcare/Sys/Brooklyn
Department
Type
DUNS #
084087808
City
Brooklyn
State
NY
Country
United States
Zip Code
11209