Author + information
- Jason D. Roberts, MD and
- Michael H. Gollob, MD⁎ ()
- ↵⁎University of Ottawa Heart Institute, Inherited Arrhythmia Clinic and Arrhythmia Research Laboratory, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada
Dr. Bjerregaard challenges the inclusion of 5 of 61 patients used in our analysis of reported cases of short-QT syndrome (SQTS) (1). We commend him on the considerable amount of time spent reviewing these cases and focusing on the relevance of their inclusion. Dr. Bjerregaard suggests that cases 23 and 49 are the same patient and that we have reported the patient twice but with “different ages and QT intervals.” His rationale for arriving at this conclusion is unclear. These patients are reported from different published reports, without any indication of having been previously described, and their differing QT intervals reflect the values quoted directly from these reports. With regard to patient #46, Dr. Bjerregaard is concerned about the terminology used in describing this patient's clinical event and the fact that his mother carries the same KCNH2 gene mutation (E50D) despite having a normal corrected (QTc) interval. This patient (QTc intervals ranging from 349 to 381 ms) had a sudden loss of consciousness in the absence of a prodrome, resulting in a motor vehicle accident. After cardiac evaluation, clinically his event was attributed to a sudden arrhythmia with spontaneous reversion, consistent with the concept of an aborted cardiac arrest. Dr. Bjerregaard's concern regarding a gene carrier demonstrating a normal phenotype is quite surprising, as this is a common observation in virtually all inherited arrhythmia conditions. The E50D mutation has never previously been observed and was absent from the screening of more than 2,600 chromosomes analyzed in a healthy control cohort (2). In collaboration with Dr. Charles Antzelevitch, biophysical analysis of this mutation confirmed a significant gain of function consistent with previous mutations reported in patients with SQTS.
The remaining 3 patients (patients #59 to #61) of concern to Dr. Bjerregaard were reported to have a novel KCNH2 gene mutation (R1135H). Biophysical studies demonstrated a significant gain of function of the mutant protein consistent with the SQTS phenotype in these 3 patients (3). One of these patients was also reported to have a “Brugada-type” electrocardiographic (ECG) pattern, although the 12-lead electrocardiogram was not published. Our view is that it is extremely unlikely that this patient had a type 1 Brugada ECG pattern, required to conclude a Brugada phenotype, and that the observed Brugada-type ECG pattern more likely reflected the nonspecific type 2 or 3 pattern. The KCNH2 gene, which has been the subject of analysis in inherited arrhythmias for more than 15 years, has never been associated with a type 1 Brugada ECG pattern.
More relevant to the challenge of diagnosing the SQTS is the issue of QTc ranges that may be associated with the condition. Dr. Bjerregaard suggests that QT interval correction should be avoided and that instead, analysis of the absolute QT interval should be restricted to periods when the heart rate approximates 60 beats/min, and he suggests that Holter monitoring would be useful. We do not believe that this approach is feasible in clinical practice and do not advocate using Holter monitors for the evaluation of QT intervals. All currently reported SQTS cases have reported the QTc interval, and although the use of the Bazett correction formula has certain limitations, these limitations are minimized when appropriate reference ranges of “normal” are considered. As described in our report, numerous large epidemiologic studies have reported the QTc interval range in thousands of subjects, providing a useful resource of the normal distribution of QTc intervals on resting 12-lead electrocardiography in the general population.
Last, Dr. Bjerregaard emphasizes that QTc intervals “as low as 340 to 350 ms…have been observed for years without reports of any increased risk for sudden cardiac death.” This comment is rather naive, as the majority of patients with long-QT syndrome and QTc intervals in excess of 480 ms diagnosed later in life have led asymptomatic and prosperous lives. This does not reflect the fact that a significant proportion of patients with long-QT syndrome with similar QTc intervals have succumbed to the tragedy of a premature sudden death. In addition, we would reiterate that a diagnosis of SQTS using the diagnostic criteria cannot be made based on a QTc interval in isolation and requires the inclusion of relevant clinical and genetic information.
Despite the negative perspective offered by Dr. Bjerregaard, we believe that our diagnostic criteria will allow a thoughtful and systematic evaluation of patients potentially harboring the SQTS. The use of a diagnostic scorecard will assist in bringing uniformity to the diagnosis of this rare condition, as it has for other conditions, such as arrhythmogenic right ventricular cardiomyopathy, for which a single clinical test or observation cannot define the disease. Certainly, this approach should be favored over personal opinion.
- American College of Cardiology Foundation
- Gollob M.H.,
- Redpath C.J.,
- Roberts J.D.
- Kapa S.,
- Tester D.J.,
- Salisbury B.A.,
- et al.