Prolonged QTc interval and insula in patients with ischemic stroke: Inductive or abductive reasoning?

While a great emphasis has been placed on pathophysiological mechanisms underlying the long QT syndromes (LQTS), both congenital and acquired forms, little attention has been focused on the mechanisms whereby a brain damage could induce changes in the QTc interval. Until now, there has been no precise explanation for the frequently observed relationship between acute cerebrovascular events and QTc interval prolongation. Many excellent studies with inductive reasoning proposed QTc effects of insular cortex stimulation [ 1 Oppenheimer S. Cerebrogenic cardiac arrhythmias: cortical lateralization and clinical significance. Clin Auton Res. 2006; 16 ([Review]): 6-11 Crossref PubMed Scopus (224) Google Scholar , 2 Oppenheimer S.M. Gelb A. Girvin J.P. Hachinski V.C. Cardiovascular effects of human insular cortex stimulation. Neurology. 1992; 42: 1727-1732 Crossref PubMed Google Scholar ] Few and controversial studies with abductive reasoning investigated an association between prolonged QTc and ischemic insular damage. Every judgment, however, results from inference. In a study by Christensen et al. [ [3] Christensen H. Boysen G. Christensen A.F. Johannesen H.H. Insular lesions, ECG abnormalities, and outcome in acute stroke. J Neurol Neurosurg Psychiatry. 2005; 76: 269-271 Crossref PubMed Scopus (134) Google Scholar ] no relation was confirmed between insular lesions and prolonged QTc interval, but the QTc cut-off value was not reported. In a paper by Tatschl et al. [ [4] Tatschl C. Stollberger C. Matz K. et al. Insular involvement is associated with QT prolongation: ECG abnormalities in patients with acute stroke. Cerebrovasc Dis. 2006; 21: 47-53 Crossref PubMed Scopus (50) Google Scholar ] the authors concluded that QTc prolongation was present mostly among patients with small infarcts of the insular region, but exclusion criteria (heart disease, previous neurological disease or intracranial injury, QT-prolonging drugs, complete bundle branch blocks) were not proposed. Moreover, in this study the QTc was considered abnormal whenever its duration, measured in lead II only, exceeded 440 ms (men) and 460 ms (women) and 227 patients were excluded for missing data. However, it is commonly recognized that precordial leads, especially V3–V4, are most reliable for assessing a long QT interval. The aim of this study is to define the relationship between long QTc and insular damage in the clinical setting of ischemic stroke, when the QTc interval evaluation is made according to the proposed sex-specific cut-points and exclusion criteria. We retrospectively reviewed 125 consecutive patients with ischemic stroke admitted to the Verona City Hospital from January 2012 to December 2013. Exclusion criteria were: 1) heart disease; 2) previous neurological disease or intracranial injury; 3) QT-prolonging drugs; 4) congenital long-QT syndrome; 5) cardiac pacing; and 6) complete bundle branch blocks. 47 patients who did not meet admission criteria were excluded from the study (11 had ischemic heart disease, 12 had complete bundle branch blocks, 7 had cardiac pacemaker, 17 were taking QT-prolonging drugs). All patients presented clinical signs of ischemic stroke and this diagnosis was systematically confirmed by a CT scan. None of the patients were treated with thrombolysis. The diagnosis of stroke was assessed according to the World Health Organization definition of stroke [ [5] A classification and outline of cerebrovascular diseases. Stroke. Sep-Oct 1975; 6: 564-616 Crossref PubMed Google Scholar ]. Computed tomography was performed on admission to determine brain infarct size and localization. For the purpose of analyses we stratified the stroke patients into 2 subgroups according to the presence of insular involvement. The clinical severity of the stroke was assessed according to modified Rankin scale (mRS) [ [6] Van Swieten J.C. Koudstaal P.J. Visser M.C. Schouten H.J. Van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1998; 5: 604-607 Google Scholar ]. A prolonged QTc, by using the Bazett's formula, was defined as greater than 450 ms for men and greater than 470 ms for women [ 7 Yap Y.G. Camm A.J. Drug induced QT prolongation and torsades de pointes. Heart. 2003; 89: 1363-1372 Crossref PubMed Scopus (733) Google Scholar , 8 Goldenberg I. Moss A.J. Zareba W. QT interval: how to measure it and what is “normal”. J Cardiovasc Electrophysiol. 2006; 17: 333-336 Crossref PubMed Scopus (409) Google Scholar ]. QTc duration was: normal in 26 male (≤450 ms) and 27 female (≤470 ms) patients; and long in 12 male and 13 female patients. Continuous data are presented as mean ± 2 standard deviations, and categorical variables are described as percentages. Comparisons of all measurements were made by using the un-paired t test and chi square test as appropriate. Univariate analysis was used to evaluate the association between QT interval and clinical variables. Given the relatively low number of observations we chose bivariate analysis to investigate the association between insular involvement (independent variable) and QT (dependent variable) independently of one variable for each model. The overall population consisted of 78 patients (51% females; mean age 74 ± 14 years). The mean QTc interval was 449 ± 31 ms but a wide range was observed: 388 to 534 ms. Clinical characteristics of the population divided according to insular involvement are shown in Table 1. Of note, patients with insular involvement had higher mRS and a significantly prolonged QTc (57%) compared to those without insular damage (26%). Table 1Comparison of stroke patients with and without insular involvement. Insular involvement (n = 14) No insular involvement (n = 64) P-value Univariate analysis with QTc interval Bivariate analysis with insular damage and QTc interval Age (years), mean ± SD 78 ± 11 73 ± 14 0.2 R: 0.4 P = 0.0003 P = 0.03 Sex, male/female, n 4/10 34/30 0.2 R: −0.22 P = 0.04 P = 0.03 Modified Rankin scale 3.6 ± 1.5 2.7 ± 1.1 0.02 R: 0.38 P = 0.0006 P = 0.07 Heart rate (beats/min) 84 ± 22 84 ± 22 0.9 R: 0.37 P = 0.0007 P = 0.007 QTc 468 ± 26 445 ± 31 0.01 K (mEq/L) 3.8 ± 0.4 3.9 ± 0.5 0.3 R: −0.34 P = 0.0002 P = 0.04 Atrial fibrillation (%) 42.8 33.3 0.3 R: −0.4 P = 0.0001 P = 0.03 Univariate associations between variables and QTc. In the last column the level of significance of the association between insular involvement and QTc is reported independently of the variable listed in the same row. Open table in a new tab Univariate associations between variables and QTc. In the last column the level of significance of the association between insular involvement and QTc is reported independently of the variable listed in the same row.