Heart disease in all its forms, including heart attacks and coronary artery disease, is the number 1 cause of death for people in the United States, cutting across the boundaries of sex, age, and racial background. The following statistics from the Centers for Disease Control shed some light on the broad and costly impact of heart disease:
- One person dies every 36 seconds in the United States from cardiovascular disease.
- About 655,000 Americans die from heart disease each year—that’s 1 in every 4 deaths.
- Heart disease costs the United States about $219 billion each year from 2014 to 2015.3 This includes the cost of health care services, medicines, and lost productivity due to death.
One of the most pernicious forms of heart disease is coronary artery disease. Although this disease takes multiple forms, essentially all coronary disease is caused by atherosclerosis, which according to heart.org is “a condition that develops when a substance called plaque builds up in the walls of the arteries. This buildup narrows the arteries, making it harder for blood to flow through. If a blood clot forms, it can block the blood flow. This can cause a heart attack or stroke.”
Most of the treatment protocols and therapeutic medications for coronary artery disease have aimed at reducing the blockages or restrictions caused by atherosclerosis, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, which reduce heart enlargement. There are also medications that address issues with blood clots, such as antiplatelets, anticoagulants, and clot-dissolving drugs.
However, the most common approach to coronary artery disease focuses on reducing cholesterol circulating in our blood supply, thereby reducing the opportunity for atherosclerosis to occur. And when diet and exercise are not enough, doctors often recommend statins, a class of drugs that reduces the cholesterol load, thereby potentially diminishing the buildup of plaque in our blood vessels.
Statins were a boon to the prevention of cardiovascular disease because they not only reduced circulating cholesterol, but have a number of other positive health benefits related to cardiovascular health.
In fact, recent research indicates, “Statins confer cardiovascular protection not only by reducing the cholesterol levels but also by decreasing LDL-cholesterol oxidation, promoting the stabilization of the atheroma plaque, inhibiting endothelial dysfunction and vascular smooth muscle proliferation, and reducing platelet activity.” These so-called “downstream effects” help improve not only overall cardiovascular rates, but are associated with reducing morbidity in people with cardiovascular disease.
Yet, none of these therapies actually get to the root cause of coronary disease, which doctors and scientists have long-suspected has a genetic component that predisposes people to developing atherosclerosis.
As cardiologist and Associate Professor of Medicine and Genetics at Washington State University, St Louis, Nathan O. Stitziel, MD, PhD points out” “A major goal of treatment for cardiovascular disease has appropriately been focused on lowering cholesterol levels. But there must be causes of cardiovascular disease that are not related to cholesterol — or lipids — in the blood. We can decrease cholesterol to very low levels, and some people still harbor residual risk of future coronary artery disease events. We’re trying to understand what else is going on, so we can improve that as well.”
Dr. Stitziel and his colleagues at The Stitziel Lab, headquartered in Washington State University, are involved in studies of “human genetic variation underlying Mendelian and complex forms of cardiovascular disease.” The lab prides itself on utilizing a “ . . . range of cutting edge next-generation genomic techniques to map causal disease genes, dissect mechanisms and pathways underlying disease, and apply insights from our studies to improve clinical care and human health.”
Armed with this technology and framework, Dr. Stitziel and other researchers have isolated a specific gene called SVEP1 that appears to be behind the creation of a protein “. . . that drives the development of plaque in the arteries.” In their research with mice, specimens that were “ . . . missing one copy of SVEP1 had less plaque in the arteries than mice with both copies.” Specifically, Stitziel and his colleagues concluded that their research “ . . .provide(s) evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque.”
This has wide ranging implications for the future trajectory of treatment for coronary disease.
One of those implications addresses the vascular smooth muscle cells. These cells, found in our blood vessels, are responsible for contracting and relaxing the vasculature. When these cells become inflamed, they make accumulated plaque less stable, and this instability is dangerous because if it breaks free in the form of a blood clot, it can lead to a heart attack or a stroke.
This inflammation, as Stitziel and his team uncovered, is driven by the protein he and his team discovered. AsIn-Hyuk Jung, PhD, one of the scientists that worked on the SVEP-1 study stated, “In animal models, we found that the protein induced atherosclerosis and promoted unstable plaque. We also saw that it increased the number of inflammatory immune cells in the plaque and decreased collagen, which serves a stabilizing function in plaques.”
The bottom line is that by using genetic methods to reduce the presence of this, or other inflammatory proteins, we could drastically reduce the prevalence of coronary artery disease. This genetic-driven approach, known as genome-wide association studies (GWAS), is part of broader efforts to address a variety of health issues and diseases.
This research base is crucial to the future of medical therapies in general, and coronary artery disease, in particular. As recent review on the genetics of coronary artery disease concludes, “A familial component contributes to cardiovascular disease (CVD) susceptibility, but it was not until the emergence of genome-wide association studies (GWAS) that genetic loci have been identified that displayed consistent associations with coronary artery disease (CAD) across multiple cohorts.”
Jared S. Elenbaas, a doctoral student in Stitziel’s lab, corroborates this perspective, saying, “The human genetic data showed a naturally occurring wide range of this protein in the general population, suggesting that we might be able to alter its levels in a safe way and potentially decrease coronary artery disease.”
This genetic orientation that connects inflammation to specific proteins led Stitzie and his fellow researchers to selectively reduce the protein in the arterial walls of mice, which will ultimately reduce the chances of them developing atherosclerosis. If this approach can be applied to humans, we may be able to eliminate the genetic factors which predispose people to developing coronary artery disease.
Slowly but surely, evidence is emerging that understanding the influence of SVEP-1 is becoming an important piece of the puzzle to ameliorating coronary artery disease and the multiple health complications that are associated with it. A recent New England Journal of Medicine publication found that “The identification of a disease-associated missense variant in SVEP1 points to a potentially novel genetic mechanism leading to atherosclerosis.”
And there is reason to be optimistic about the potential of gene therapy in general to redefine how the medical profession treats heart disease. According to Sander van Deventer, supervisor of the development of alipogene tiparvovec (Glybera), the first gene therapy to gain regulatory approval, “. . . gene therapy to reduce the risk of cardiovascular disease could become a reality within 5 years — initially targeted to help people with high cholesterol” and that technologies for “delivering gene editing can be safe, effective and work in the long term.”
This is particularly encouraging, because SVEP1 and its associated proteins have also been implicated in other disease processes, such as Alzheimer’s/dementia diseases. And the fight against Alzheimer’s has been difficult and mostly without consequential gains, because despite “decades of intensive study, there are no treatments that can slow the disease process, let alone stop or reverse it.”
Josef Coresh, MD, PhD, MHS, George W. Comstock Professor in the Department of Epidemiology at the Bloomberg School and lead researcher of the study Proteins that predict future dementia, Alzheimer’s risk, identified, concluded, “Some of these proteins we uncovered are just indicators that disease might occur, but a subset may be causally relevant, which is exciting because it raises the possibility of targeting these proteins with future treatments.”
And although overall the incidence of coronary artery disease has fallen dramatically since the 1970s, the COVID-19 pandemic may be responsible for a reversal in this trend. Wendy Susan Post, M.D., M.S., Director of Cardiovascular Research, Division of Cardiology, and Professor of Medicine at Johns Hopkins Heart and Vascular Institute writes:
Heart damage can also be due to high levels of inflammation circulating in the body. As the body’s immune system fights off the virus, the inflammatory process can damage some healthy tissues, including the heart. Coronavirus infection also affects the inner surfaces of veins and arteries, which can cause blood vessel inflammation, damage to very small vessels and blood clots, all of which can compromise blood flow to the heart or other parts of the body.
Remember that SVEP-1 is associated with an inflammatory process, especially as it relates to our blood vessels. This inflammatory process is also a major component of severe COVID-19 infection.
As Dara K. Lee Lewis, M.D. writes in her blog post COVID-19 and the heart: What have we learned?: “In the severe form of COVID-19, the body’s immune system overreacts to the infection, releasing inflammatory molecules called cytokines into the bloodstream. This so-called ‘cytokine storm’ can damage multiple organs, including the heart.” So, it stands to reason that genetic therapy in the form of an SVEP-1 modification, may play a role in mitigating the damage done to the heart by reducing the damage created by the inflammatory response caused by the responsible proteins.
And a recent study may just show a connection to “an increased risk of respiratory failure in COVID-19 patients” and the presence of the inflammatory protein associated with SVEP-1. This is right in line with a plethora of research that shows inflammation of various body systems and organs may be the root of most diseases. To be clear, I am not referring to acute inflammation, which is short term and needed to heal injuries, but rather chronic inflammation.
In the chronic type of inflammation, “. . . the immune system continues to pump out white blood cells and chemical messengers that prolong the process,” says Dr. Robert H. Shmerling, medical editor of Understanding Inflammation from Harvard Health Publishing and an associate professor of medicine at Harvard Medical School. “From the body’s perspective, it’s under consistent attack, so the immune system keeps fighting indefinitely,” says Dr. Shmerling.
And unlike acute inflammation, chronic inflammation leads to a constellation of diseases, including heart disease, diabetes, cancer, arthritis, and bowel diseases like Crohn’s disease and ulcerative colitis. There are also symptoms of chronic inflammation that some people may erroneously associate with natural aging, such as general muscle weakness, fatigue, rashes, and chest pain.
Of course, improving your diet and exercising regularly can allay chronic inflammation, so long term, these measures, along with other life-style changes, such as reducing stress and improving sleep, are always recommended. However, the promise of gene therapy in general, and research into SVEP-1, portends to the potential of major breakthroughs for treating coronary artery disease along with other diseases associated with deleterious inflammatory processes.
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