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A Clinical Study Starting from an Encounter with a Patient

The story of this clinical study began with a patient I encountered as a post-graduate student on night duty at Juntendo University Hospital in 1989. The patient was diagnosed as idiopathic ventricular fibrillation ( IVF ) with incomplete right bundle branch block and a bizarrely shaped ST segment elevation in V 1-3 . He had a history of sick sinus syndrome ( SSS ) one year earlier. Three years after that encounter, the Brugada brothers reported eight patients with IVF whose ECG findings were very similar to those of my patient, and this syndrome was later named Brugada syndrome ( BrS ) . It is now known that there are many individuals with BrS in Japan and across Asia, and regrettably the first patient’s report was not released in Japan. With the later progress in genomic research it has become apparent that a single gene mutation could be a cause of both BrS and SSS. We have begun a clinical study of the association between BrS and SSS and have published several papers about this issue. My first patient with BrS and SSS has been doing well without syncope for over 30 years.


A Clinical Study Starting from an Encounter with a Patient
After graduating from the graduate medical school, I encountered a very impressive patient while I was on night duty at Juntendo University Hospital in 1989. The patient was a 42-year-old man, medical nurse, who was transferred to our hospital after experiencing several episodes of syncope. One year prior to his referral, he had been diagnosed with sick sinus syndrome (SSS) and received a cardiac pacemaker at our hospital, however, he suffered from a recurrence of syncope and was brought to our hospital by ambulance. After arriving, he lost consciousness and had convulsions in the emergency room, but recovered spontaneously. The results of physical examinations and a chest X-ray were unremarkable. The ECG showed sinus rhythm with a slight PR prolongation of 0.26 sec., incomplete right bundle branch block (RBBB), and a bizarrely shaped ST segment elevation in V 1-3 (Figure 1, top). However, he reported experiencing no chest pain. Two hours after his hospitalization, the patient suddenly developed polymorphic ventricular tachycardia followed by ventricular fibrillation (VF) (Figure 1, bottom). The delivery of an external DC shock successfully recovered sinus rhythm.
Laboratory findings, echocardiographic examination, and cardiac catheterization revealed no abnormality. We thus diagnosed as idiopathic VF (IVF). After the administration of prophylactic medical therapy, i.e., mexiletine and propranolol, VF did not recur. The ST elevation in the right precordial leads was gradually reduced after defibrillation, but it persisted.
Three years later, during a study-abroad program at the Good Samaritan Hospital, Los Angeles, California, I found an article by the Brugada brothers that surprised me 1) . The Brugada brothers reported the eight patients of IVF with RBBB and persistent ST segment elevation, 1) whose ECG findings were very similar to those of the above-described patient.
Soon after returning to Japan, I wrote a case report about the patient I encountered at Juntendo University Hospital as I described before that was published in 1993 in Japanese Heart Journal. 2) I had searched for similar cases at related hospitals, but did not find any. This syndrome was later named "Brugada syndrome (BrS)". One day, Dr. Osamu Yamanaka, my senior by one year, asked me "Is there any relationship between VF and sinus node dysfunction?" At that time, I had not noticed the association of the two arrhythmias. Five years later (1998), the first genetic mutation of BrS was reported in Nature. 3) I was glad as our case report was cited in the report's references.
In 2003, I encountered another patient with BrS at Juntendo Shizuoka Hospital. The patient was a 62-year-old man who was referred for syncope. He had also experienced two episodes of nocturnal awakening with urinary incontinence. His ECG showed a typical Brugada-type ST elevation in the right precordial leads (Figure 2, left). During his hospitalization, ECG monitoring revealed asymptomatic episodes of sinus pause at midnight with a maximum duration of 6.6 seconds (Figure 2, right). However, during the electrophysiologic study, the patient's sinus node function was normal and ventricular tachyarrhythmia could not be induced by the programmed electrical stimulation. On the basis of the multiple syncopal episodes including the nocturnal awakening with urinary incontinence and the typical ECG finding for BrS, the patient received with an implantable cardioverter-defibrillator (ICD), which successfully converted an episode of VF that occurred 2 months later ( Figure 3). I remembered that the first case of BrS that I observed at Juntendo University Hospital had also suffered from sinus node dysfunction. I found several papers which revealed that a single muta-   tion in SCN5A could be a cause of both BrS and SSS. [4][5][6] At that point in time, we had only five patients diagnosed as having BrS at Juntendo University Hospital and affiliated hospitals, and three of the five patients coincidentally suffered from sinus node dysfunction. Then, I reported our three cases of BrS concomitant with sinus node dysfunction in 2005. 7) At Juntendo University Hospitals, although the number of patients with BrS was very limited, there were many patients with SSS. We were able to study 487 consecutive patients implanted with a pacemaker for SSS at Juntendo University Hospital or Shizuoka Hospital during the period from 1971 to 2004. We retrospectively analyzed the patient's ECG results obtained just before the pacemaker implantations, and we identified a Brugada-type ECG in 14 patients (2.87%) including four (0.82%) with type 1 (the coved-type) and 10 (2.05%) with type 2 (the saddleback-type). 8) Remarkably, two of the four patients with a type 1 ECG had experienced a spontaneous episode of VF. In 2010, we reported that the prevalence of typical Brugada-type (type 1) ECG among SSS patients seems to be higher compared to the general population: 0.82% in SSS patients and 0.05%-0.28% in adults of the general population. 8 In 2018, we published the clinical review "Brugada  syndrome and sinus node dysfunction" in the Journal of Arrhythmia as a compilation of our studies concerning BrS and SSS 9) . My first BrS patient encountered during my night shift at Juntendo University Hospital had a documented episode of VF 32 years earlier, and he has been doing well without syncope or an ICD operation since then. His recent ECG, recorded 30 years after his last VF episode, no longer showed Brugada-type ECG findings ( Figure 5).

Epilogue
I described a narrative concerning my clinical studies of BrS and SSS. These studies were inspired by a patient I encountered at Juntendo University Hospital. I believe that case report is very important for academic career because clinical studies may start with a clinical question in case presentation.