Gene Mutation Could Prime the Heart To Fail

Highlights

• A multinational study shows that mutation in the titin gene can lead to cardiac effects on health individuals and not just among dilated cardiomyopathy patents.
• The cardiac gene mutation results in a compromised state where a second hit could prime the heart to fail
• The study provides a better understanding of dilated cardiomyopathy and provides support for the use of genetic tests to identify the condition.

Latest research has shown that mutations in a gene that codes for the protein titin affect the heart in heathy individuals. This multinational study has dispelled earlier belief that this mutation affected people with dilated cardiomyopathy only. The genetic mutation in the titin gene occurs in 1% of the world’s population. Scientists have now revealed that this gene could prime the heart to fail. In the event of a genetic or environment factors triggering a second hit, the mutation in the titin gene could result in a compensated state.

The study was conducted by

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

Dilated Cardiomyopathy

It is a disease that affects the heart muscle, most importantly the left ventricle. It leads to

• Ventricular dilation
• Systolic function impairment
• Reduction in myocardial contractility
• Nearly 30-40% have familial inheritance pattern
• It is normally an autosomal dominant form of inheritance
• Nearly 40 genes are associated with this condition, out of which 25% of familial and 18% of sporadic cases are found to be due to mutations in the titin gene.
• Affects 1 in 250 people
• Heart muscles become weak and cannot pump blood.
• Alcohol consumption, use of illegal drugs and certain infections are some of the other causes for this condition.

The study’s co-author, Professor Stuart Cook elaborated on the finding of their study “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.” Dr. Cook is a SingHealth Duke-NUS Academic Medical Centre’s Tanoto Foundation Professor of Cardiovascular Medicine.

The study involved studying titin gene mutations in 2495 patients with dilated cardiomyopathy. Molecular level studies as well as studies on heart function were carried out using two rat models. Apart from these studies, the researchers also studied the cardiac gene mutations in 1409 healthy adults. These studies also included 2D and 3D cardiac magnetic resonance imaging which were used to provide high resolution images of heart size and shape.

Impairment of the Heart Function

The mutation in the titin gene occurs in 1% of the population but it was believed to result only in dilated cardiomyopathy. However, the current study has found that there could be impairment of heart function.

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The study conducted on 1,409 healthy adults is detailed by Dr Antonio de Marvao who is a Clinical Lecturer at MRC Clinical Sciences Centre and The Imperial College London “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 carry 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.”

Benefits of the Study

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• The study provides a better understanding about dilated cardiomyopathy
• New targets for drug therapies were identified
• The condition may be diagnosed confidently using genetic tests
• Variants in gene mutations that caused the most common form of dilated cardiomyopathy were identified.
• The study involved collaboration between UK, Singapore and German research groups, resulting in a better understanding from various ethnicities.

Dr James Ware who is a clinical Senior Lecturer added “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 analysing aggregated genetic and clinical data from a network of collaborating units around the world.”

Cardiac genetic tests are currently available to test for mutations in 174 genes and 17 conditions. This new study on mutation in the titin gene will aid in identifying one more inherited cardiac condition using genetic testing procedures .

Though genetic risk factors are not the sole causative agents, an understanding of the effect produced by these genes will aid in adopting a lifestyle better suited to manage these health conditions.

References:

1. What Causes Cardiomyopathy? - (https://www.nhlbi.nih.gov/health/health-topics/topics/cm/causes)

Source-Medindia