Author + information
- Robert Roberts, MD∗ ()
- ↵∗Address for correspondence:
Dr. Robert Roberts, International Society of Cardiovascular Translational Research, University of Arizona College of Medicine-Phoenix, 550 East Van Buren Street, Phoenix, Arizona 85004.
Although the heart has only 1 function—to contract and relax in an orderly and regulated rhythm—it requires the integration of many complex ionic and neuronal activities. The eloquence and simplicity of the pattern displayed by a normal electrocardiogram, whether it be conduction through the atria and atrioventricular node exhibited by the PR interval, or conduction through the bundle of HIS, right and left bundles exhibited by the QRS belies the timely coordination of multiple ions moving in and out of specialized cardiac tissue. The overriding hormonal and neuronal regulation of the timing and direction of the various ionic currents is no more or less important than the structural platform provided by the specialized conduction tissue. Analysis of various electric currents, whether carried by sodium, chloride, calcium, or more rare ions, has given rise to a greater understanding and the development of more appropriate and safer drugs. This analysis has been helped tremendously over the past 2 decades by the discovery of genes responsible for rare cardiovascular single gene disorders. Fortunately, there have been several such disorders that, upon discovery of the responsible gene, enabled elucidation of the molecular mechanism. These have included Wolff-Parkinson-White syndrome, long QT syndrome, Brugada syndrome, and others (1).
Roberts et al. (2) in this issue of JACC: Clinical Electrophysiology report on the discovery of a gene responsible for bundle branch reentrant ventricular tachycardia (BBRVT). BBRVT is a life-threatening situation often associated with the structural heart disease, primarily dilated cardiomyopathy. The surface electrocardiogram shows ventricular tachycardia with a wide QRS and if the His–Purkinje re-entry focus is conducted retrograde through the right bundle, a pattern of left bundle branch block is observed. A right bundle branch pattern would be observed if the conduction were in the opposite direction. It has been observed that such cases sometimes occur in young people with no apparent structural heart disease. The investigators postulated that this may be due to a genetic defect and the importance of separating this form of BBRVT from that, secondary to structural heart disease, could have significant diagnostic and therapeutic applications. They formed a network involving 6 centers in North America and enrolled individuals <60 years of age with BBRVT in the absence of structural heart disease. The diagnosis of BBRVT was confirmed by invasive electrophysiologic studies, showing the presence of a His bundle signal preceding ventricular activation with changes in the H-H interval driving changes in the V-V interval.
The investigators identified 6 patients (4 males) with BBRVT with normal ventricular size and function. Each case of BBRVT was confirmed by electrophysiologic studies. The mean age of diagnosis was 26 years. Only 1 patient had a family history of cardiac conduction disease. Four presented with BBRVT and 2 with atrial ventricular block that subsequent developed into BBRVT. Four patients on electrophysiologic studies showed a pattern of left bundle branch block with 2 patients showing both right and left bundle branch blocks. All 6 patients responded to catheter ablation and after an average follow-up of 6 years, there was no recurrence of ventricular tachycardia.
Genetic analysis detected a mutation in the gene encoding for the sodium channel in 2 patients and a mutation in the lamina gene in 1 patient. Despite comprehensive DNA sequencing, no mutations were identified in the other 3 cases. Because these are single probands without results in siblings or other family members, the mutations could not be confirmed as causative by the traditional method of showing the mutant gene segregates only with affected individuals. It is important to analyze the evidence claiming these mutations are causative. In case 1, there was a missense mutation in the sodium gene (SCN5A) consisting of a substitution of alanine for glycine in the carboxy terminus of the sodium ion channel. The glycine is well-conserved throughout the mammalian species. In vitro studies in mammalian cells exhibit one-half maximal activation voltages for homozygous and heterozygous forms of this mutation, indicating that the mutation induced a change in the function of the gene. The other mutation in the sodium gene occurred in a splice site, which is predicted to lead to deletion of 32 amino acids from the ion channel. Electrophysiologic studies indicated a complete loss of function of the sodium channel. The mutation in the third case was a missense mutation in the LMNA gene, substituting leucine for valine in the lamina protein. Interestingly, mutations in LMNA have been well-recognized as a cause of dilated cardiomyopathy. In fact, this case developed dilated cardiomyopathy a few years later and died while awaiting cardiac transplantation. The presence of mutations in essential genes, which severely alter their function, together with the clinical features strongly indicate these 3 mutations are causative for BBRVT.
In the present study, the investigators have documented 3 of 6 cases of BBRVT to be due to mutations in the SCN5A and LMNA genes. This establishes that at least 1 cause of BBRVT is genetic. It remains to be determined whether BBRVT associated with dilated cardiomyopathy is secondary to structural heart disease or due to a genetic defect. The case of BBRVT described by the investigators due to a lamina mutation, who subsequently developed dilated cardiomyopathy, strongly suggests a genetic cause. BBRVT is a cause of sudden cardiac death and can occur early in life; the average age of presentation in these cases was only 26 years. Thus, screening for these mutations and other de novo mutations in the case of BBRVT is strongly recommended, as should next of kin once the mutation in a new case is identified. This is a significant finding for sudden cardiac death and one that is associated with curative therapy. All 6 cases of BBRVT had abnormal surface electrocardiograms, 4 had definitive ventricular conduction defects, and the remaining 2 a prolonged QRS or abnormal axis. Although one cannot generalize from 6 cases, individuals presenting with ventricular conduction abnormalities without structural heart disease must now be considered for the new genetic etiology. This is a significant finding because it is associated with sudden cardiac death and can be avoided by catheter ablation.
The present report is further inspiration to pursue the genes responsible for single gene disorders. It is claimed that there are 7,000 single gene disorders, of which 1 or more genes have been discovered for over 4,000 of these disorders (3). Knowing the precise molecular mechanism for a disorder such as BBRVT, which causes sudden death, can only improve our diagnostic, therapeutic, and pathophysiologic armamentarium.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Roberts has reported that he is a member of the Scientific Advisory Board for Cumberland Pharmaceuticals.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2017 American College of Cardiology Foundation
- Marian A.J.,
- Brugada R.,
- Roberts R.
- Roberts J.D.,
- Gollob M.H.,
- Young C.,
- et al.