Genes And Cardiovascular Disease: When Can Testing Be A Tool?

Pankaj Arora, MD

Heart disease doesn't play fair. Lifelong smokers who never exercise may live well into their 80s on fast food, while vegetarian joggers can die suddenly when their hearts give out.

Advances in diagnosis, surgical and nonsurgical interventions, preventive medications and healthier lifestyles are saving thousands of lives that would have been lost only a few years ago. Yet a big part of the equation determining who dies of heart disease, who lives and how well is found in the genes we inherit at birth.

Now that genomic testing is becoming more affordable, especially for genes in targeted segments associated with specific disorders, clinical practices need to know when it makes sense to look for heart disease in a patient's genes. How soon will we be able to use genetic testing to detect individual heart health risks and choose the most effective approach to prevention and treatment?

"At this point in our understanding of genetics and heart disease, it all comes down to the potential for making a difference in management and outcome," researcher and UAB assistant professor or cardiology Pankaj Arora, MD said. "What can genetic testing tell us beyond what we can learn from a family history, clinical examination and the diagnostic tools we already have?"

The actionable information we can gather through testing differs with the type of heart disease. In some cardiomyopathies and electrical disorders, one gene, if switched on, can have a large effect in determining whether a patient develops the disorder. Association studies have already identified genetic links in a number of these disorders.

However, the disease processes that lead to most heart attacks come from the cumulative impact of many different combinations of genes with a small effect that can be switched on or off by epigenetic triggers like lifestyle, environment and illness. We haven't learned enough yet to look at the many variables and reliably predict the risks for a patient.

"In screening families with a history of sudden death at an early age, in clarifying the diagnosis for some causes of heart failure to plan the most effective course of treatment, and to identify which medication is likely to be effective in which patient, there are cases where genetic testing can be helpful," Arora said.

In families with a history of rhythm disturbances where a close relative has died suddenly at an early age or been diagnosed with an electrical disorder, screening others who may share the gene is a consideration. This could be particularly important in young people before they participate in high intensity sports or go into the military or another physically demanding or high stress career.

Many of the causes of heart failure are idiopathic or difficult to determine. Screening for genes linked to specific types of heart failure may be helpful in choosing the most effective treatment and predicting the likely course of the disease as it progresses.

"When a patient needs a blood thinner, a genetic test can tell us which medication should be most effective," Aurora said. "What we are learning about genes and how they relate to heart disease is also helping us identify pathways and new research targets for medications that could prevent or slow the progression of the disease."

Arora's current research focuses on natriuretic peptides (NPs), a hormone produced by the heart.

"A deficiency in NP signaling seems to promote cardiometabolic disease," he said. "This could be an important therapeutic target. Learning more about how the NP axis works could lead to medications that could modulate cardiometabolic risks."

How genetic polymorphisms and their variants contribute to the risk for heart disease has been a major target for research around the world. An accumulating body of data from some of these investigations is offering interesting insights that could be helpful as clinical practice moves more and more toward precision medicine.

For example, APO E, or apolipoprotein E, which is a polymorphism that has been researched in relation to Alzheimer's Disease, also seem to have strong links to coronary artery disease. Alleles 2, 3 and 4 show significant differences in how they interact with LDL, fats, sugars, alcohol and even different types of exercise. The most troubling links are to APO E 4/4, where the patient received copies of allele 4 from both parents. This combination is at extremely high risk for Alzheimer's and high cholesterol that can be difficult to control. Someone with APO E 2/2 would have a low risk for Alzheimer's, but possible difficulties in how lipids and sugars are handled. An APO E 4/4 patient and an APO E 2/2 patient could have opposite and even counterproductive responses to the standard advice of avoiding fats, exercising and having a glass of red wine.

However, DNA is not destiny. A large study at Massachusetts General of people with a high genetic risk for heart disease found that a healthy lifestyle cut the risk of dying from heart disease in half over the next 10 years.

Progress is also being made in gene therapies to edit variants that contribute to cardiomyopathies and in using stem cells to regrow damaged heart muscle.

As research into the genetic underpinnings of cardiovascular disease makes rapid leaps forward, it is an exciting time full of hope for at last defeating America's number one killer. A growing understanding of genes and how they work could soon give us the keys to preventing heart disease and helping the body heal itself.


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APO E-2, APO E-4, cardiomypathy, cardiovascular polymorphisms, cardiovascular rhythm disturbances, Genes and cardiovascular disease, MD, natriuretic peptides, NPs, Pankaj Arora, sudden death, UAB


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