Titin Gene Mutation Increases Risk of Heart Failure

Previously thought to affect only patients with dilated cardiomyopathy, researchers have discovered that truncating variants in the gene for the protein titin also adversely affect heart function in healthy individuals, placing them at higher risk under conditions of stress.

The finding, from a multinational study by researchers from Singapore, the UK, and Germany, may help understand a long observed paradox: that many people carry this mutation with no apparent effect. The key, the team now suggests, is that the hearts of such people may be “primed to fail” if they also suffer from a second relevant condition, whether a genetic or environmental stress.

The study was led by the National Heart Centre Singapore in collaboration with Duke-NUS Medical School, Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC).

“We now know that the heart of a healthy individual with titin gene mutation lives in a compensated state and that the main heart pumping chamber is slightly bigger. Our next step is to find out the specific genetic factors or environmental triggers, such as alcohol or viral infection, that may put certain people with titin mutations at risk of heart failure,” said co-senior author Prof. Stuart Cook, of Sing Health Duke-NUS Academic Medical Centre.

Dr. Antonio de Marvao, clinical lecturer at Imperial College London (London, UK) and MRC, added: “Our previous work showed that mutations in the titin gene are very common in people diagnosed with heart failure. Around 1% of the general population also carries these mutations, but until now it wasn't known if these are ‘silent' gene changes or changes that can adversely affect the heart. Using state-of-the-art cardiac MRI, we created extremely detailed 3D “virtual hearts” from the scans of 1,409 healthy adults. We found that those with mutations have an enlarged heart, and in a pattern similar to that seen in heart failure patients. This may impact as many as 35 million people around the world. In future work we will investigate if the heart function of our volunteers is indeed impaired, by MRI scanning them as they exercise on a bike.”

Dr James Ware, clinical senior lecturer at Imperial College London and MRC, said: “For patients with dilated cardiomyopathy, this study has improved our understanding of the disease, revealed possible new targets for drugs and other new therapies, and importantly has improved our ability to diagnose the condition confidently with genetic tests. This work required a very collaborative approach, with many institutions involved in assembling genetic data from tens of thousands of individuals. The finding that titin mutations are affecting the hearts of so many otherwise apparently healthy people worldwide, and potentially increasing their risk of heart failure, poses even pressing questions, such as why some people with these mutations seem to do well in the long term, while others do not. Fortunately, we are in a strong position to tackle these questions from lots of different angles, by analyzing aggregated genetic and clinical data from a network of collaborating units around the world.”

The researchers studied the effects of titin gene mutations in 2,495 patients with dilated cardiomyopathy. They also generated two rat models to understand the impact of these mutations on the molecular level and heart function. In addition, cardiac gene sequencing tests were performed in 1,409 healthy volunteers, coupled with 2D and 3D cardiac magnetic resonance imaging (MRI) that gave high-resolution information on the heart size and shape of the study subjects. The data collected gave major new insights allowing to better understand the variants that represent the commonest genetic cause of dilated cardiomyopathy, yet are prevalent in the general population.

First-author Prof. Sebastian Schäfer, National Heart Centre Singapore, explained: “We could directly show the impact of the mutations on the titin protein production which has an impact on the heart. Even though the heart appears healthy initially, it reacts to this genetic stress on many levels such as changes to its gene expression and energy source. The heart can compensate and its cardiac function remains fine until an additional stressor occurs. That’s when the heart fails, as it no longer has the capacity to react the same way a healthy heart does.”

Co-senior author Prof. Norbert Hübner, Max Delbrück Center, added: “By using a variety of genomic approaches we showed that the RNA that is produced from the actual titin allele which carries the mutation, is degraded in the cells of the heart. This led to important insights on how these titin mutations operate.”

Currently, patients with inherited cardiac conditions can undergo a cardiac genetic test to screen for 174 genes in 17 such conditions, for diagnosis and thereby for prescribing effective treatment.

The study, by Schafer S, Marvao A, et al, was published online November 21, 2016, in the journal Nature Genetics.

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