Previous research showed that faulty titin gene variants were common in patients with a form of heart disease called dilated cardiomyopathy (DCM). DCM is a common inherited condition in which the heart muscle becomes enlarged and weakened and cannot pump blood efficiently. Yet around one percent of the general population carry the variations in their genome with no apparent effects.
Now researchers from the UK, Singapore, and Germany have identified how healthy carriers are affected by the faulty variants. They have published their research in Nature Genetics.
'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,' said Dr Antonio de Marvao, clinical lecturer at Imperial College London and the MRC Clinical Sciences Centre.
The research also indicates that abnormal stress could cause carriers to develop DCM.
Dr Sebastian Schäfer, the first author of the study and a senior research fellow at the National Heart Centre in Singapore, explained: 'Even though the heart appears healthy initially, it reacts to this gene 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.'
The team, led by Dr Stuart Cook, analysed almost 2500 people with DCM using heart imaging and genetic analysis, and found strong associations with faulty, 'truncated' variants of the titin gene.
The researchers then sequenced the titin gene in more than 1400 healthy volunteers and used MRI, magnetic resonance imaging, to analyse the shape and size of their hearts. As expected, around one percent of volunteers had faulty variants. However, they also had slightly enlarged hearts, similar to those seen in heart failure patients.
Finally, the researchers generated two rat models with faulty titin genes. They found that although the hearts of the rats appeared healthy, putting the heart under abnormal stress triggered DCM.
In the future, the team is hoping to find out the genetic or environmental factors – such as pregnancy, alcoholism, or viruses – that may put certain people with variations in the titin gene at a higher risk of heart failure.
'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,' said Dr James Ware, a clinical senior lecturer in genomic medicine at Imperial College London and the MRC Clinical Sciences Centre.