Heart disease has been the most common cause of death globally for the past 20 years. Ischaemic heart disease causes 16% of deaths, and 1% of the population has an inherited heart condition. Gene technology has created new insight into the causes. A new study shows that mutations in the code for a receptor in the cells of the myocardium (heart muscle) increase the risk of cardiac arrest. This information enables the children who may have inherited the mutation to be screened, which can save their lives through drug treatment or a specialized pacemaker.
People can be incredibly grief-stricken when they lose a loved one. When a child or adolescent dies for inexplicable reasons, parents and other family members experience even more pronounced feelings of emptiness at the sudden very premature death. Unfortunately, many young people still die from sudden cardiac arrest, but researchers in a major international collaboration have now identified a new genetic cause for the development of a type of cardiac arrest that affects children and adolescents and is often fatal.
“We have shown that certain loss-of-function mutations in the cardiac ryanodine receptor (RyR2) can lead to a previously unknown inherited heart condition we have called cardiac ryanodine receptor calcium release deficiency syndrome (CRDS). This can cause severe arrhythmia. Although diagnosis requires advanced examination, our findings enable us to screen children who may have inherited the mutation. Although the mutation is not always fatal, we can offer them drug treatment or an implantable cardioverter defibrillator, an advanced pacemaker for preventing cardiac arrest,” explains Henrik Kjærulf Jensen, Clinical Professor, Department of Clinical Medicine, Aarhus University and Consultant Cardiologist, Department of Cardiology, Aarhus University Hospital.
Catecholaminergic polymorphic ventricular tachycardia is an inherited heart condition exacerbated by exertion or stress that can cause severe arrhythmia from RyR2 gain-of function mutations. RyR2 controls the release of calcium ions from the sarcoplasmic reticulum in the myocardium, which is essential for excitation-contraction coupling in the heart. Mutations were already known to cause RyR2 gain-of-function. The problem has been mutations that reduce the release of RyR2 (loss-of-function).
“RyR2 gain-of-function can be reproduced through exercise stress testing, in which we measure electrocardiogram patterns during training on a bicycle or treadmill. However, some people who have survived sudden cardiac arrest have RYR2 loss-of-function, but we did not observe such ECG patterns in their bicycle test. We therefore decided to investigate whether we could discover any genetic patterns among these people,” says Henrik Kjærulf Jensen.
The large international team led by Wayne Chen, Professor, Department of Physiology and Pharmacology, University of Calgary, Canada therefore used a programmed electrical stimulation protocol to clinically and genetically assess individuals who had survived sudden cardiac arrest and had a loss-of-function RyR2 mutation.
“We found six families who had this RyR2 loss-of-function mutation, which was strongly linked with the risk of cardiac arrest and sudden cardiac death and can be triggered without physical exertion or emotional stress,” explains Henrik Kjærulf Jensen.
Preventing severe arrhythmia
The researchers developed a knock-in mouse model expressing an RyR2 loss-of-function mutation to study how it affects the heart. The mice underwent the same exercise stress testing as humans (on a much smaller treadmill). The researchers now have a mouse model test system for characterizing other mutations that inhibit the RyR2 receptor in the human heart.
“This also enables us to induce severe arrhythmia in mice and determine whether any characteristic electrophysiological patterns recur that can be used to identify life-threatening arrhythmia,” says Henrik Kjærulf Jensen.
Then the researchers showed through electrophysiological studies that quinidine and flecainide can prevent severe arrhythmia from developing in mice.
“Quinidine is rarely used for humans, but it shows us the types of molecular mechanisms involved in mice and that the condition may be alleviated. For people, we use flecainide to treat classical catecholaminergic polymorphic ventricular tachycardia caused by RyR2 gain-of-function mutations, and we also use well-proven beta-blockers. An implantable cardioverter defibrillator is another option,” explains Henrik Kjærulf Jensen.
The researchers have both discovered and explained the mechanisms behind a previously unknown syndrome associated with sudden cardiac death. They have also developed a potential invasive electrophysiological test and identified drug treatment options, and this is why Henrik Kjærulf Jensen and his collaborators and research group are focusing on integrating basic and clinical research.
“We started by examining the hearts of zebrafish fetuses using CRISPR-Cas9 gene-editing technology. Because they are transparent, we can observe heart changes directly and also take electrocardiograms, so we can study how specific mutations affect zebrafish before assessing and investigating how they affect people,” says Henrik Kjærulf Jensen.
The main purpose of the projects is ultimately to reduce the risk and thus the tragedy of sudden cardiac death.
“We can achieve this by optimizing the diagnosis and treatment of people with inherited heart conditions. In future, we will be able to much better carry out clinical and molecular genetic diagnosis of the children of parents with an inherited heart condition and thus tailor treatment to each individual,” explains Henrik Kjærulf Jensen.
This precision or personalized medicine will enable doctors and parents to make far more qualified decisions on how to treat children and adolescents.
“The same genetic mutations affect people differently, and people vary in how they feel about risk. This is similar to the decision about whether to take out insurance or not, or to cycle with or without a helmet. The new studies will give everyone the opportunity to choose between the best options, including medicine, a specialized pacemaker or no treatment,” concludes Henrik Kjærulf Jensen.