Around 1 per cent of the population carry a faulty gene which could trigger a dangerous heart condition in seemingly healthy people, if the heart is placed under abnormal stress, such as through pregnancy or alcoholism, according to research part-funded by the British Heart Foundation (BHF) and published in Nature Genetics1.
The researchers at Imperial College London and the MRC Clinical Sciences Centre (MRC-CSC), who studied both mice and people, believe the findings suggest that around 75 million people worldwide could be at risk of developing heart failure if their hearts are placed under abnormal stress. It may be that the stress caused by pregnancy, a viral infection of the heart, alcoholism or high blood pressure could trigger the heart problems.
The international collaboration, which included BHF-funded Professor Stuart Cook, involved looking at rats with a faulty version of a gene called titin. They found that although the rats appeared healthy, placing abnormal stress on the heart triggered a rare heart muscle condition called dilated cardiomyopathy (DCM), which causes heart failure2.
DCM is a disease of the heart muscle where it becomes stretched and thin, and is unable to pump blood around the body efficiently. It affects 1 in 250 people in the UK and is the most common cause of heart transplant3.
The researchers also looked at the genes of 1,400 healthy adult volunteers and created detailed 3D computer models using scans of their hearts at the MRC-CSC in London. As expected, 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 the findings in mice 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.
Research is now underway to find out which genetic factors or environmental triggers may put people with titin mutations at risk of heart failure.
Professor Stuart Cook, who led the study, is head of the Cardiovascular Genetics and Genomics group within Genetics & Imaging at the National Heart and Lung Institute (NHLI) and Professor of Clinical & Molecular Cardiology at Imperial College London. He said:
"We now know that the heart of a healthy individual with the titin gene mutation lives in a compensated state and that the heart's main pumping chamber is slightly bigger.
"Our next step is to find out which are the specific genetic factors or environmental triggers, such as alcohol or viral infection, may put certain people with titin mutations at risk of heart failure."
Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, which part-funded the study, said:
"Most people with titin mutations live a long and healthy life, but some will develop DCM, a heart condition which can lead to heart failure. This excellent research shows us that there is much more to this condition than we originally thought.
"We can now use this knowledge to identify preventable or avoidable factors that trigger DCM in those who carry titin mutations and also develop new treatments for DCM which target the genetic basis of the disease."
The study was supported by the British Heart Foundation, Medical Research Council Clinical Sciences Centre, NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, Tanoto Foundation, National Medical Research Council Singapore, and SingHealth Duke-NUS Institute of Precision Medicine, among others.
Article: Titin truncating variants affect heart function in disease cohorts and the general population, Schafer, Marvao et al.,