A mutation in the gene ‘titin’ can affect the hearts of some healthy people, show findings published in Nature Genetics today. Their hearts can compensate for the mutation and function as usual, but it may make them “primed to fail”. If put under abnormal stress, such as through pregnancy or alcoholism, they may develop heart disease.

The findings come from an international study involving groups from the UK, Singapore and Germany and may help scientists to understand a paradox: namely that around one per cent of the world’s population, some 35 million people, carry this genetic mutation with no apparent effect. “We now know that the heart of a healthy individual with titin gene mutations 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,” says Professor Stuart Cook, of the MRC Clinical Sciences Centre (CSC), based at Imperial College London, and a co-leader of the international study.

The titin gene produces a protein, also called titin, and which is one of the largest proteins in our bodies. It has been known that mutations in titin play a role in the inherited heart condition dilated cardiomyopathy, in which the heart muscle becomes weakened, enlarged and cannot pump blood efficiently. It was previously thought that mutations in titin affect only those with this condition.

“Our previous work showed that mutations in the titin gene are very common in people diagnosed with heart failure. Around 0.5% of the general population also carry these mutations in a part of their genome that affects the heart, but until now it wasn’t known if these are ‘silent’ gene changes or changes that can adversely affect the heart,” says Dr Antonio de Marvao, also at the CSC.

“Using state-of-the-art cardiac Magnetic Resonance Imaging (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.”

Of the healthy volunteers in the study, 15 people (around 1 per cent) had the titin gene mutation. From looking at the 3D heart models, the scientists found that healthy people with the titin mutations had a slightly enlarged heart, compared with those without the mutations. This supports findings in rats which suggest titin mutations, even in the absence of DCM, are having an impact on the heart but that this starts in a very subtle way.

“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,” says Dr James Ware of the CSC. “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 more 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 analysing aggregated genetic and clinical data from a network of collaborating units around the world.”

3D statistical model of the left ventricle of the heart of 1400 healthy volunteers. Left: the heart while filling with blood. Right: the heart as it contracts to pump blood around the body. In red are areas of the heart enlarged in those with titin mutations when compared to those without.

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

Assistant Professor Sebastian Schäfer, Senior Research Fellow at the National Heart Centre Singapore and who is the first author of the paper 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.”

Professor Norbert Hübner, Professor of Cardiovascular and Metabolic Sciences at the MDC and co-senior author, detailed: “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 for patients with inherited cardiac conditions, they can undergo a cardiac genetic test that will screen them of 174 genes in 17 such conditions to diagnose the exact condition and gene, to prescribe effective treatment.

The study is funded by Tanoto Foundation, National Medical Research Council Singapore, SingHealth Duke-NUS Institute of Precision Medicine, Medical Research Council Clinical Sciences Centre UK, NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust and Imperial College London and British Heart Foundation UK, among others.

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