Abstract
Patients with connective tissue diseases (CTDs) may have prolonged corrected QT interval which indicates increased risk for ventricular arrhythmias. However, a more sensitive measure of ventricular repolarization, T-peak-to-end (Tpe) interval, has not been studied in CTDs. We aimed to investigate the relationship between ventricular repolarization abnormalities and anti-Ro52-positivity in subjects with connective tissue diseases (CTDs). We enrolled patients with anti-Ro52-positive CTDs, ANA-positive CTDs, and healthy subjects in this cross-sectional study. We excluded conditions potentially affecting the QT interval. We compared the ECG measures between the groups and performed analyses to define factors associated with ventricular repolarization measures. 15 ANA and anti-Ro52-positive, 39 ANA-positive and anti-Ro52-negative, and 22 healthy subjects were enrolled. None of the subjects had rhythm or conduction disturbances. Corrected QT intervals were similar between the groups. Tpe (84, 77.3, and 69.4 msn, respectively) and QT-dispersion (40, 27.2, and 20.1 msn, respectively) were higher in anti-Ro52-positive subjects compared with the ANA-positive and healthy subjects. Anti-Ro52 titers were correlated with Tpe and QT-dispersion (r = 0.52 and p < 0.001 for each). ANA and anti-Ro52-positivity were independently associated with higher Tpe (OR = 7.7, p = 0.001 and OR = 6.9, p = 0.001, respectively), corrected Tpe (OR = 11.3, p = 0.001 and OR = 8.4, p = 0.003, respectively), QT dispersion (OR = 7, p = 0.008 and OR = 13, p < 0.001, respectively), and QTc dispersion (OR = 9.1, p = 0.001 and OR = 14.1, p < 0.001, respectively). This study provides evidence that ANA positivity, especially when concomitant anti-Ro52-positivity is present, significantly deteriorates ventricular repolarization. The aforementioned ventricular repolarization abnormalities may render these subjects susceptible to serious rhythm or conduction disorders in the setting of predisposing conditions.
Similar content being viewed by others
References
Lazzerini PE, Capecchi PL, Laghi-Pasini F (2010) Anti-Ro/SSA antibodies and cardiac arrhythmias in the adult: facts and hypotheses. Scand J Immunol 72(3):213–222. doi:10.1111/j.1365-3083.2010.02428.x
Ambrosi A, Sonesson SE, Wahren-Herlenius M (2014) Molecular mechanisms of congenital heart block. Exp Cell Res 325(1):2–9. doi:10.1016/j.yexcr.2014.01.003
Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL (2000) QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum 43(5):1049–1053. doi:10.1002/1529-0131(200005)43:5<1049:aid-anr13>3.0.co;2-x
Lazzerini PE, Acampa M, Guideri F, Capecchi PL, Campanella V, Morozzi G, Galeazzi M, Marcolongo R, Laghi-Pasini F (2004) Prolongation of the corrected QT interval in adult patients with anti-Ro/SSA-positive connective tissue diseases. Arthritis Rheum 50(4):1248–1252. doi:10.1002/art.20130
Lazzerini PE, Capecchi PL, Guideri F, Bellisai F, Selvi E, Acampa M, Costa A, Maggio R, Garcia-Gonzalez E, Bisogno S, Morozzi G, Galeazzi M, Laghi-Pasini F (2007) Comparison of frequency of complex ventricular arrhythmias in patients with positive versus negative anti-Ro/SSA and connective tissue disease. Am J Cardiol 100(6):1029–1034. doi:10.1016/j.amjcard.2007.04.048
Lazzerini PE, Capecchi PL, Acampa M, Morozzi G, Bellisai F, Bacarelli MR, Dragoni S, Fineschi I, Simpatico A, Galeazzi M, Laghi-Pasini F (2011) Anti-Ro/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity. Arthritis Care Res (Hoboken) 63(10):1463–1470. doi:10.1002/acr.20540
Lazzerini PE, Department of Medical Sciences SaN, University of Siena, Italy, lazzerini7@unisi.it, Capecchi PL, Department of Medical Sciences SaN, University of Siena, Italy, Laghi-Pasini F, Department of Medical Sciences SaN, University of Siena, Italy (2015) Long QT syndrome: an emerging role for inflammation and immunity. Front Cardiovasc Med. doi:10.3389/fcvm.2015.00026
Lazzerini PE, Capecchi PL, Laghi-Pasini F (2015) Isolated atrioventricular block of unknown origin in adults and anti-Ro/SSA antibodies: clinical evidence, putative mechanisms, and therapeutic implications. Heart Rhythm 12(2):449–454. doi:10.1016/j.hrthm.2014.10.031
Bourré-Tessier J, Urowitz MB, Clarke AE, Bernatsky S, Krantz MJ, Huynh T, Joseph L, Belisle P, Bae SC, Hanly JG, Wallace DJ, Gordon C, Isenberg D, Rahman A, Gladman DD, Fortin PR, Merrill JT, Romero-Diaz J, Sanchez-Guerrero J, Fessler B, Alarcón GS, Steinsson K, Bruce IN, Ginzler E, Dooley MA, Nived O, Sturfelt G, Kalunian K, Ramos-Casals M, Petri M, Zoma A, Pineau CA (2015) Electrocardiographic findings in systemic lupus erythematosus: data from an international inception cohort. Arthritis Care Res (Hoboken) 67(1):128–135. doi:10.1002/acr.22370
Massie C, Hudson M, Tatibouet S, Steele R, Huynh T, Fritzler MJ, Baron M, Pineau CA, CSRG (2014) Absence of an association between anti-Ro antibodies and prolonged QTc interval in systemic sclerosis: a multicenter study of 689 patients. Semin Arthritis Rheum 44(3):338–344. doi:10.1016/j.semarthrit.2014.07.001
Nomura A, Kishimoto M, Takahashi O, Deshpande GA, Yamaguchi K, Okada M (2014) Prolongation of heart rate-corrected QT interval is a predictor of cardiac autonomic dysfunction in patients with systemic lupus erythematosus. Rheumatol Int 34(5):643–647. doi:10.1007/s00296-013-2718-z
Antzelevitch C (2001) T peak-Tend interval as an index of transmural dispersion of repolarization. Eur J Clin Invest 31(7):555–557
Goldner B, Brandspiegel HZ, Horwitz L, Jadonath R, Cohen TJ (1995) Utility of QT dispersion combined with the signal-averaged electrocardiogram in detecting patients susceptible to ventricular tachyarrhythmia. Am J Cardiol 76(16):1192–1194
Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, Deckers JW, Kingma JH, Sturkenboom MC, Stricker BH, Witteman JC (2006) Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 47(2):362–367. doi:10.1016/j.jacc.2005.08.067
Panikkath R, Reinier K, Uy-Evanado A, Teodorescu C, Hattenhauer J, Mariani R, Gunson K, Jui J, Chugh SS (2011) Prolonged Tpeak-to-tend interval on the resting ECG is associated with increased risk of sudden cardiac death. Circ Arrhythm Electrophysiol 4(4):441–447. doi:10.1161/circep.110.960658
Yue Y, Castrichini M, Srivastava U, Fabris F, Shah K, Li Z, Qu Y, El-Sherif N, Zhou Z, January C, Hussain MM, Jiang XC, Sobie EA, Wahren-Herlenius M, Chahine M, Capecchi PL, Laghi-Pasini F, Lazzerini PE, Boutjdir M (2015) Pathogenesis of the novel autoimmune-associated long-QT syndrome. Circulation 132(4):230–240. doi:10.1161/circulationaha.115.009800
Abu-Shakra M, Urowitz MB, Gladman DD, Gough J (1995) Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 22(7):1259–1264
Buyon JP, Clancy RM, Friedman DM (2009) Autoimmune associated congenital heart block: integration of clinical and research clues in the management of the maternal/foetal dyad at risk. J Int Med 265(6):653–662. doi:10.1111/j.1365-2796.2009.02100.x
Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL, Jacobsen SJ, Gabriel SE (2005) Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 52(2):402–411. doi:10.1002/art.20853
Lazzerini PE, Capecchi PL, Acampa M, Galeazzi M, Laghi-Pasini F (2014) Arrhythmic risk in rheumatoid arthritis: the driving role of systemic inflammation. Autoimmun Rev 13(9):936–944. doi:10.1016/j.autrev.2014.05.007
Costedoat-Chalumeau N, Amoura Z, Hulot JS, Ghillani P, Lechat P, Funck-Brentano C, Piette JC (2005) Corrected QT interval in anti-SSA-positive adults with connective tissue disease: comment on the article by Lazzerini et al. Arthritis Rheum 52(2):676–677. doi:10.1002/art.20845
Cardoso CR, Sales MA, Papi JA, Salles GF (2005) QT-interval parameters are increased in systemic lupus erythematosus patients. Lupus 14(10):846–852
Milovanovic B, Stojanovic L, Milicevik N, Vasic K, Bjelakovic B, Krotin M (2010) Cardiac autonomic dysfunction in patients with systemic lupus, rheumatoid arthritis and sudden death risk. Srp Arh Celok Lek 138(1–2):26–32
Bourre-Tessier J, Clarke AE, Huynh T, Bernatsky S, Joseph L, Belisle P, Pineau CA (2011) Prolonged corrected QT interval in anti-Ro/SSA-positive adults with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 63(7):1031–1037. doi:10.1002/acr.20470
Teixeira RA, Borba EF, Pedrosa A, Nishioka S, Viana VS, Ramires JA, Kalil-Filho R, Bonfá E, Martinelli Filho M (2014) Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus. Europace 16(6):887–892. doi:10.1093/europace/eut290
Sgreccia A, Morelli S, Ferrante L, Perrone C, De Marzio P, De Vincentiis G, Scopinaro F (1998) QT interval and QT dispersion in systemic sclerosis (scleroderma). J Int Med 243(2):127–132
Adlan AM, Panoulas VF, Smith JP, Fisher JP, Kitas GD (2015) Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis. J Rheumatol 42(3):421–428. doi:10.3899/jrheum.140861
Eickhoff CS, Lawrence CT, Sagartz JE, Bryant LA, Labovitz AJ, Gala SS, Hoft DF (2010) ECG detection of murine chagasic cardiomyopathy. J Parasitol 96(4):758–764. doi:10.1645/ge-2396.1
Saribayev M, Tufan F, Oz F, Erer B, Ozpolat T, Ozturk GB, Akin S, Saka B, Erten N, Tascioglu C, Karan A (2014) Corticosteroid treatment normalizes QTc prolongation and improves heart block in an elderly patient with anti-Ro-positive systemic lupus erythematosus. Aging Clin Exp Res 26(3):337–339. doi:10.1007/s40520-013-0168-9
Santos-Pardo I, Martinez-Morillo M, Villuendas R, Bayes-Genis A (2013) Anti-Ro antibodies and reversible atrioventricular block. N Engl J Med 368(24):2335–2337. doi:10.1056/NEJMc1300484
Villuendas R, Olive A, Junca G, Salvador I, Martinez-Morillo M, Santos-Pardo I, Pereferrer D, Zamora E, Bayes-Genis A (2014) Autoimmunity and atrioventricular block of unknown etiology in adults: the role of anti-Ro/SSA antibodies. J Am Coll Cardiol 63(13):1335–1336. doi:10.1016/j.jacc.2013.10.086
Santos-Pardo I, Villuendas R, Salvador-Corres I, Martinez-Morillo M, Olive A, Bayes-Genis A (2015) Anti-Ro/SSA antibodies and cardiac rhythm disturbances: present and future perspectives. Int J Cardiol 184:244–250. doi:10.1016/j.ijcard.2014.11.002
Gupta P, Patel C, Patel H, Narayanaswamy S, Malhotra B, Green JT, Yan GX (2008) T(p-e)/QT ratio as an index of arrhythmogenesis. J Electrocardiol 41(6):567–574. doi:10.1016/j.jelectrocard.2008.07.016
Piccirillo G, Cacciafesta M, Lionetti M, Nocco M, Di Giuseppe V, Moise A, Naso C, Marigliano V (2001) Influence of age, the autonomic nervous system and anxiety on QT-interval variability. Clin Sci (Lond) 101(4):429–438
Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, Burashnikov A, Di Diego J, Saffitz J, Thomas GP (1999) The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 10(8):1124–1152
Wolk R, Stec S, Kulakowski P (2001) Extrasystolic beats affect transmural electrical dispersion during programmed electrical stimulation. Eur J Clin Invest 31(4):293–301
Rautaharju PM, Zhou SH, Gregg RE, Startt-Selvester RH (2011) Electrocardiographic estimates of action potential durations and transmural repolarization time gradients in healthy subjects and in acute coronary syndrome patients–profound differences by sex and by presence vs absence of diagnostic ST elevation. J Electrocardiol 44(3):309–319. doi:10.1016/j.jelectrocard.2010.11.009
Barbhaiya C, Po JR, Hanon S, Schweitzer P (2013) Tpeak–Tend and Tpeak–Tend/QT ratio as markers of ventricular arrhythmia risk in cardiac resynchronization therapy patients. Pacing Clin Electrophysiol 36(1):103–108. doi:10.1111/pace.12031
Kilicaslan F, Tokatli A, Ozdag F, Uzun M, Uz O, Isilak Z, Yiginer O, Yalcin M, Guney MS, Cebeci BS (2012) Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe obstructive sleep apnea. Pacing Clin Electrophysiol 35(8):966–972. doi:10.1111/j.1540-8159.2012.03439.x
Gordon PA, Rosenthal E, Khamashta MA, Hughes GR (2001) Absence of conduction defects in the electrocardiograms [correction of echocardiograms] of mothers with children with congenital complete heart block. J Rheumatol 28(2):366–369
Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM, Huong DL, Denjoy I, Vauthier D, Sebbouh D, Fain O, Georgin-Lavialle S, Ghillani P, Musset L, Wechsler B, Duhaut P, Piette JC (2004) Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group. Arthritis Rheum 50(10):3187–3194. doi:10.1002/art.20554
Motta M, Rodriguez-Perez C, Tincani A, Lojacono A, Chirico G (2007) Outcome of infants from mothers with anti-SSA/Ro antibodies. J Perinatol 27(5):278–283. doi:10.1038/sj.jp.7211688
Lazzerini PE, Capecchi PL, Boutjdir M, Laghi-Pasini F (2015) Comment on “absence of an association between anti-Ro antibodies and prolonged QTc interval in systemic sclerosis: a multicenter study of 689 patients”. Semin Arthritis Rheum 44(5):e16–e17. doi:10.1016/j.semarthrit.2014.10.002
Acknowledgments
We thank Ercan Cegilli, MD (Department of Cardiology, Uludag University School of Medicine) for his help in measurement of ECG data.
Funding
We thank Bursa Kidney Foundation for their funding support.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Ethical statement
The ethical committee of Uludag University School of Medicine approved the study, and we carried out the study in accordance with the Declaration of Helsinki and its later amendments.
Informed consent
All of the participants provided informed consent.
Conflict of interest
None.
Rights and permissions
About this article
Cite this article
Tufan, A.N., Sag, S., Oksuz, M.F. et al. Prolonged Tpeak–Tend interval in anti-Ro52 antibody-positive connective tissue diseases. Rheumatol Int 37, 67–73 (2017). https://doi.org/10.1007/s00296-016-3488-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00296-016-3488-1