Author + information
- Pedro Brugada, MD, PhD∗ ()
- ↵∗Address for correspondence:
Dr. Pedro Brugada, UZ Brussel-VUB, Cardiovascular Division, Laarbeeklaan 101, Brussels, Vlaams-Brabant 1090, Belgium.
In this issue of the Journal, Mazzanti et al. (1) report the therapeutic effects of hydroquinidine (HQ) in a small series of patients with the rare inherited arrhythmia known as short QT syndrome (SQTS) (2). Because of the rarity of the disease, the number of patients included in this study is necessarily limited. The study lacks a control series receiving placebo. No mention is made of the previous study by Gaita et al. (3) on the effects of HQ on SQTS, also in a small series of patients. The follow-up period is extremely short for an inherited (and thus permanently present) arrhythmia. Despite these limitations and others that I will point out, this study is an important one, as it complements our understanding of genetically determined cardiac arrhythmias, while also pointing out some important practical problems in the management of rare diseases, like the unavailability of old drugs, such as HQ.
That HQ prolongs the QTc interval has been known for decades. It is thus logical to postulate that prolongation of the QT interval with HQ could have a beneficial effect on arrhythmias caused by a shortened repolarization pattern, as in SQTS. With 73 patients available and with only about 200 patients reported in the published medical data, Mazzanti et al. (1) theoretically had on their hands almost one-third of all worldwide known SQTS patients. Regretfully, only 1 in 5 patients accepted participation in their HQ study, and this is a major limitation. Of the 17 included patients, only 6 (35%) had previously experienced an aborted sudden cardiac death (ASCD). The QTc was below 320 ms in only 4 patients (a QTc interval suggested by others as the real cutoff point for diagnosis of SQTS, rather than the 360-ms QTc interval used in this study). A possibly pathology-related mutation was found in only 2 patients (11%), and only 1 of these 2 patients was symptomatic. This raises the question of whether are we dealing with 17 or, at the most, 6 patients with a real SQTS. HQ prolonged the QTc interval in all patients, but the most dramatic changes (see Figure 1 and Table 1 in the paper by Mazzanti et al. ) occurred in the 5 patients with basal QTc intervals below 325 ms. A simple calculation shows that HQ prolonged the QTc interval by a mean of 23% in patients with a basal QTc below 325 ms, whereas the mean prolongation was only 14% in individuals with a basal QTc above 325 ms. This 14% prolongation of the QTc is about the same percentage observed in patients without SQTS treated with HQ for other reasons (4). The mean maximal dose of HQ did not differ between the 2 groups. Thus, the diagnosis of SQTS should be reconsidered in almost two-thirds of the patients in this study.
Although a randomized trial with a placebo group would be of interest, it is obvious that such a study was not possible due to the limited number of patients. An event rate of 0% on HQ at a mean follow-up of 6 years may be meaningless. Even when the exact age at the first ASCD was not given, the age at the time of diagnosis after ASCD was between 20 and 37 years. Thus, these individuals lived with SQTS without any problems for 20 to 37 years. The question is, then, how long should these patients be followed, not to prove, but merely to suggest a possible therapeutic effect of HQ? Another 20 to 37 years, or twice as long? In inherited arrhythmias like Brugada syndrome (BS), we have suggested (5), as in cancer research, that the follow-up should be until death, with clear documentation of the cause of death for all patients involved. Follow-ups of a mean of 5 months after a therapeutic intervention, as presented by others (6), are scientifically unacceptable. In this sense, Figure 3 in the paper by Mazzanti et al. (1) is misleading, as it suggests, but does not prove, a therapeutic effect of HQ. As already suggested by the investigators, a large, randomized trial is desirable with HQ compared with placebo. However, we have to realize that SQTS is a truly rare disease, and a randomized trial, although valuable, is unlikely to occur. But, after all of these considerations, are we still missing something?
We have come a long way from the time when cardiac arrhythmias were empirically treated with digoxin, or at most with a beta-blocker agent or the old antiarrhythmic drugs, like disopyramide, mexiletine, lidocaine, and HQ. Scientific advances came from the pioneering work of many who tried to understand the pathophysiological mechanisms of the arrhythmias. That Wolff-Parkinson-White syndrome was caused by an atrioventricular accessory pathway led ultimately to its surgical and later to its percutaneous cure with catheter ablation. Almost any other cardiac arrhythmia was to follow. Nowadays, ablation of the substrate is possible for almost any known cardiac arrhythmia, including some inherited ones (6). In BS, the substrate has been located at the right ventricular outflow tract, and the substrate can be ablated and modified. However, we still do not know where the substrate is located in at least 3 inherited entities: long QT syndrome, catecholamine-induced polymorphic ventricular tachycardia, and SQTS. HQ was also proposed as a possible treatment for BS. Ablation of the substrate in BS has made HQ a last choice because of high recurrence rates of arrhythmias, side effects, and problems with compliance (7). Although not yet proven in the long-term, substrate ablation may offer a real cure in BS. The question is, then, whether we can do the same in SQTS (i.e., normalize the QTc and prevent arrhythmias by localizing and modifying-ablating the substrate). In this sense, the study by Mazzanti et al. (1) may seem irrelevant and much ado about nothing, while we await the next real advances in pathophysiological understanding and curative steps. However, I saw this study as real food for thought and an important step to stimulate further research. HQ may be a short-term option for SQTS, particularly in patients with electrical storms. It also might prevent the atrial fibrillation associated with SQTS, an issue unfortunately not addressed at all in the study by Mazzanti et al. (1). Regretfully, HQ is no longer available in many countries, simply because of economic issues. Old drugs are poorly refunded by health authorities, even when they may be effective or when they may prove effective in new indications, like STQS. This is in stark contrast to the extremely high prices that industry demands for new drugs for other rare diseases.
Real progress in the understanding and treatment of SQTS will come from unmasking the substrate and modifying it (if possible). Long-term progress will come from genetic manipulation of the SQTS substrate. Meanwhile, it is good to know that we can prolong the QTc interval with HQ in SQTS, a very relevant observation if HQ is made available again.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Brugada has reported that he has no relationships relevant to the contents of this paper to disclose. Deepak L. Bhatt, MD, MPH, served as Guest Editor for this paper.
- 2017 American College of Cardiology Foundation
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