11: Inherited Cardiac Arrhythmias

Nippon Medical School’s Department of Cardiovascular Medicine boasts a long history. It is a large department with a total of approximately 200 members including those belonging to its four affiliated hospitals. Dr. Wataru Shimizu, specialist in arrhythmia, has led this historic department as a professor since April of 2013.

The reason why, out of the numerous cardiovascular diseases, Dr. Shimizu chose arrhythmia as a research theme can be traced back to an arrhythmia patient he met shortly after becoming a physician. The patient was 26 years old, the same age as Dr. Shimizu and the physician’s first patient with hereditary long QT syndrome. Dr. Shimizu says, “The patient had a history of syncope during exercise extending back to elementary school, and was clinically diagnosed with LQTS via electrocardiogram. After diagnosis I saw the patient regularly as an outpatient for nearly 30 years. It was the encounter with this patient that made me interested in hereditary arrhythmias such as hereditary LQTS; this patient provided the motivation for what would become my life’s work.”

・What is LQTS?

LQTS is an arrhythmic disease in which a ventricular tachycardia known as torsades de pointes occurs, causing a sudden loss of consciousness. Most cases are known to be hereditary. It is asymptomatic between episodes, but when episodes shift to dizziness, fainting, palpitations, dysphoria, or ventricular fibrillation, there are cases in which sudden death occurs. Diagnosis is possible when long QT appears on electrocardiograms, but there are still no fundamental treatment methods. However, with drug therapy and the implantation of Implantable Cardioverter-Defibrillators (ICDs), the number of cases of sudden death due to sympathectomy, etc. is greatly reduced.

Let us take a look at the arrhythmic fields that Dr. Shimizu has been involved in, in particular his LQTS clinical research results.

・The Japanese Multicenter Registry for Patients with Hereditary LQTS

In 1998, after becoming a doctor and finishing his studies in the US, Dr. Shimizu would be reinstated at the National Cerebral and Cardiovascular Center Hospital. However, this was the post-genome era. In other words, it was an age in which there was a challenge regarding in what way the genetic information received through molecular biology methods could be passed on to clinical sites. The period of time from the late 90s to the early 2000s was also an age in which numerous responsible genes in hereditary arrhythmia patients had been identified.

It was in the midst of this that Dr. Shimizu tirelessly performed his research and clinical activities with the goal of genetic diagnosis of hereditary arrhythmia using molecular biology methods. At the same time, starting from the year 2006, he began the Japanese Multicenter Registry for Patients with Hereditary LQTS as a research representative of Health Labour Sciences Research.

Up to the year 2013, 1,123 cases had been registered and formed into this registry centering on the most frequently identified 13 responsible genes for LQT1, LQT2, and LQT3 patients. It was this research that uncovered the triggers for heart incidences (fainting, resuscitated cardiac arrest, and sudden death) for each responsible gene.

Heart Incidences (fainting, cardio-respiratory arrest, ventricular fibrillation)
For instance, Dr. Shimizu pointed out that “It was determined that, for LQT1, there were many cases of heart incidences experienced during exercise – such as swimming. For LQT2, there were many cases of heart incidences during emotional stress or when waking up to noises while having been asleep. On the other hand, for LQT3, there were many cases of heart incidences during sleep or restful periods.” In other words, there is a possibility that one can avoid heart incidences by avoiding these kinds of characteristic triggers depending on his or her genetic type.
Dr. Shimizu states that even now, using these kinds of results, “We are performing tailor made treatments and providing lifestyle coaching for LQT1, LQT2, and LQT3 patients based on their genetic type.”

Figure 3 shows the effects of a medication known as Mexiletine, a sodium channel blocker, on a 25-year-old male LQT3 patient. After intravenously administering 125 mg of the drug to the LQT3 patient, his QTc was significantly shortened from 572ms before administration to a more ordinary 433 ms following administration. In this way, understanding medications that are selectively effective based genetic type makes it possible to implement tailor-made treatments. The selective effectiveness of β-blockers on LQT1 and LQT2 patients has also been announced.

The future of arrhythmia research

According to Dr. Shimizu, the next new trend to be aware of in hereditary arrhythmia research is research using iPS cells announced by Dr. Shinya Yamanaka in 2006. Dr. Shimizu states that “By deriving and fabricating cardiac muscle cells from the iPS cells of hereditary LQTS patients and other hereditary arrhythmia patients, we can use them for electrophysiological function analysis and chemical sensitivity testing. I believe that, this will make it possible to clarify a patient’s individual condition of variation, identify effective medications and, in the future, to lead the way to the discovery of new treatment methods.

In the past it was necessary to perform a biopsy and actually stick a patient with a needle and directly obtain cardiac muscle cells from a patient. With iPS cells, however, it is possible to make cardiac muscle cells from cells inside of blood drawing from the patient. Because of this achievement, it is possible to effectively perform related research.

Finally, Dr. Shimizu strongly stated that “I anticipate the accelerated advancement of future research through the use of iPS cells as research tools for hereditary arrhythmia patients. This iPS technology is also what will bring about individually tailor-made treatments. I would like to continue proactively being involved in this area.”