C H Unnikrishnan
Cardiovascular disease has been the largest cause of death in India for several decades. Although high blood pressure and the buildup of fat inside the artery walls, contributed by unhealthy diet, smoking, obesity and stress, are still singled out as key risk factors, recent studies flag a more serious alert on the genetic side. These studies have proved that around 4.5% of South Asian population are naturally prone to heart disease. The cause is inherited genetic mutation. Of this group, at least 10% are carriers of the same mutation from both the parents and therefore run the risk of sudden cardiac death at a very young age.
So, think before prescribing a blood thinner and giving a pat on the patient’s shoulder saying there is a “small congestion” in the heart. Do a fact check on the medical history of the patient’s family and you ought to find similar cases there, either living with the disease or involving death at a young or middle age. Go a little deeper, as such cases often need a comprehensive evaluation.
The prevalence of inherited heart diseases have been high in the country, but unfortunately it hasn’t got much attention until now. In today’s genomic era, population mapping and next-generation sequencing technologies are revealing the true and scary picture. If these studies are to be believed, around 60 million Indians carry a monogenic mutation that is responsible for serious cardiomyopathies, a frequent cause of sudden heart failure.
While at least 200 rare mutations affecting more than 20 different genes have been identified for heart disease, the mutation associated with the gene MyBPC3 or the sarcomeric gene is found to be the key factor that causes dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).
The MyBPC3 gene that provides instructions for making cardiac myosin binding protein C (cardiac MyBP-C) is found in heart muscle cells or sarcomere. This cell structure,
which is the basic unit that helps heart muscle contraction,
are made up of thick and thin filaments. The overlapping thick and thin filaments attach to each other and release, which allows the filaments to move relatively to one another so that muscles can contract with a regular rhythm to pump blood to the body. MyBP-C also regulates the speed of cardiac muscle contract.
Because individuals who have heritable cardiomyopathies with MyBP-C defects have a disorganised sarcomeric structure and late-onset symptoms, MYBPC3 has been identified for increased risk of heart failure by either hypertrophic or dilated cardiomyopathies.
Earlier studies had identified variant(s) in MyBPC3 associated with increased risk of heart failure by screening DNA samples from individuals with cardiomyopathies in India. This was also established in various other studies with small and large patient, postmortem cases and controlled healthy individual groups.
“More than 1.5 billion people in South Asia are correctly viewed not as a single large population, but as many small endogamous groups.
Dr K Thangaraj, Senior Principal Scientist, CCMP, Hyderabad.
“There are multiple challenges here. First is the low awareness about inherited heart diseases, the other two are the cost and general inertia in approaching these cases in a comprehensive way,
Dr Hisham Ahmed Consultant Cardiologist, AIMS Kochi
A large-scale case-control study in India 2008, published in Nature Genetics, had suggested that homozygous deletion might be associated with a severe and sometimes early-onset form of the disease, although it was found in normal individuals as well.
We started the first Cardiac Risk in Young (CRY) clinic in India in 2015. And now, we are looking at novel genetic variants involved in HCM pathology specific to India.
Dr KM Cherian Founder and Chairman, Frontier Lifeline Hospital, Chennai
In this study, which was done to assess the significance of the 25-bp deletion by MyBPC mutation, taking 800 cases and 699 controls in two groups comprising 354 individuals with cardiomyopathies (including 33 postmortem cases and 238 healthy controls matched for ancestry, age, sex and geography) 49 carried 25bp deletion, 46 as heterozygotes and three as homozygotes. Two out of the three homozygotes died as children younger than 3 years old owing to cardiomyopathies.
There were also much larger studies and surveys later to prove the effect of genetic mutation resulting in recessive diseases, including more focused studies on heart diseases. The reason for such high prevalence of recessive diseases in the South Asian population is the existence of a large number of divided population groups in the form of ethnic communities, caste groups etc. that marry only within their respective groups. Hence, even the genetic mutations associated with recessive diseases are passed on from one generation to the next as both parents are frequently carriers of the defective version.
“More than 1.5 billion people in South Asia are correctly viewed not as a single large population, but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events,” says Dr K Thangaraj, Senior Principal Scientist at Centre for Cellular and Molecular Biology, Hyderabad, who led this large study in 2016.
Less medical attention
Even as the criticality of inherited heart diseases in India is becoming more and more apparent, the local medical community is yet to pay the required attention to the issue.
“There are multiple challenges here. While the first and the most important issue is the low awareness about inherited heart diseases, the other two are the cost and practical difficulties in approaching these cases in a comprehensive way, which is essential, in a traditional hospital set-up,” says Dr Hisham Ahmed, the consultant cardiologist at Amrita Institute of Medical Sciences and Research who was instrumental in setting up the country’s first and only comprehensive hypotrophic cardiomyopathy unit at Amrita Hospital in Kochi. The center was set up in collaboration with world renowned HCM specialist Dr Barry J Maron, with genetic diagnostics support from Bangalore-based MedGenome.
According to India’s leading cardiac surgeon Dr KM Cherian, hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiomyopathies. The awareness of this condition in India is limited and specialist clinics to treat this condition are very few.
“We started the first Cardiac Risk in Young (CRY) clinic in India in 2015. And now, we are looking at novel genetic variants involved in HCM pathology specific to India,” Dr Cherian added.
Since it is a critical health issue in India, and at the same time, less focused, some hospitals have volunteered dedicated screening and treatment centres for inherited heart diseases, aided by the advanced genomic tests that have emerged of late.
“Through CRY, we are providing comprehensive care for the patients and their families affected by HCM and other forms of inherited cardiomyopathies free of cost,” says Dr Cherian.
However, there are still very few institutions in India that have a fully integrated care, including genetic screening, cardiac imaging, interventional cardiology, cardiac electrophysiology, heart failure team and specialised doctors who can handle surgeries such as septal myectomy to treat obstructive hypertrophic cardiomyopathy.
“There is also a general inertia among cardiac surgeons to focus on septal myectomy as it is an extensive procedure with comparatively less outcome,” said Dr Praveen Varma, Professor and Head of the Department of Cardiovascular & Thoracic Surgery at Amrita Institute of Medical Sciences and Research.
“We have known for long time that there are people out there at high risk for disease based just on their overall genetic variation,” says Dr Sekar Kathiresan, a well-known physician scientist,a human geneticist and the director of the Cardiovascular Disease Initiative at the Broad Institute and The Center for Genomic Medicine at Massachusetts General Hospital.
“Now, we are able to measure that risk using genomic data in a meaningful way. From a public health perspective, we need to identify these higher-risk segments of the population so we can provide appropriate care,” Dr Kathiresan commented in an August statement published on the website of Association of American Universities related to a new test that helps identify those at risk of five deadly diseases with a genetic component in the world. Among these diseases were coronary artery disease, breast cancer and type-2 diabetes.
“Now, we are able to measure that risk using genomic data in a meaningful way. From a public health perspective, we need to identify these higher-risk segments of the population so we can provide appropriate care,”
Dr Sekar Kathiresan Director, CVD Initiative, Broad Institute, and The Center for Genomic Medicine at MGH.
Many of the cardiac disorders run in the family indicating inherited genetic risk factors. Cardiac disorders can be a part of syndrome or can be isolated one. Depending upon the symptoms presentation, appropriate genetic testing can be suggested. At Metropolis, the test range varies from routine chromosomal karyotyping, FISH, Microarray to Next generation sequencing (NGS) depending upon the symptoms and patient condition.
“In the era of NGS, mutations on phenotypic basis are underway and are expected to lead to new discoveries that may translate to novel diagnostic, prognostic and therapeutic targets for the benefit of the patients,” said Dr. Shailesh Pande, Senior Medical Geneticist & Genetic Counsellor, Consultant-HOD, Dept. of Medical Genetics, Metropolis Healthcare.
Dr. Shailesh Pande
Senior Medical Geneticist, Metropolis
The mutations for different cardiomyopathies have been identified and cataloging of mutations on a phenotypic basis is underway. These efforts are expected to lead to new discoveries that may translate to novel diagnostic, prognostic and therapeutic targets, Dr Shailesh Pande added.
Meanwhile, new studies have revealed that the instance of hypertrophic cardiomayopathy in the world population is much larger than what was known earlier.
“Earlier, the world average of HCM cases was known to be one in every
500 and that has gone up to one in
every 200 people now. This could probably be representative data for
India too, or may be it is more,” alerts
Dr Hisham Ahmed.