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Solving The Riddle Of The Sphingolipids In Coronary Artery Disease

Weill Cornell Medicine investigators have uncovered a way to unleash in blood vessels the protective effects of a type of fat-related molecule known as a sphingolipid, suggesting a promising new strategy for the treatment of coronary artery disease.

In the study, published March 8 in Circulation Research, the researchers showed that boosting levels of a sphingolipid called S1P in artery-lining endothelial cells slows the development and progression of coronary artery disease in an animal model. The lead author was Dr. Onorina Laura Manzo, a postdoctoral researcher in the laboratory of Dr. Annarita Di Lorenzo, an associate professor of pathology and laboratory medicine at Weill Cornell Medicine.

Sphingolipids are named for the enigmatic sphinx of ancient mythology because their functions in biology traditionally have been somewhat mysterious. In recent years, there has been increasing evidence of their relevance in coronary artery disease; bloodstream levels of S1P, for example, are lower in patients with this condition. But the precise roles of these lipids have remained unclear.

In the new study, the researchers sought a better understanding of those roles -- and of sphingolipids' potential as therapeutic targets. Despite the availability of cholesterol-lowering drugs and other interventions, coronary artery disease -- the underlying cause of most heart attacks and many strokes -- continues to be the world's leading cause of mortality, affecting more than 20 million people in the United States alone.

Using a novel mouse model developed by the same group, the researchers found that blood pressure-related stress on arteries -- which eventually will induce coronary artery disease -- triggers an increase in S1P production in endothelial cells, as part of a protective response. This response normally is only temporary, but deleting a protein called NOGO-B, which inhibits S1P production, allows the rise in endothelial S1P production to be sustained -- and made the animals much more resistant to coronary artery disease and associated mortality.

Another key finding is related to a different group of sphingolipids called ceramides. Prior studies have linked coronary artery disease to high bloodstream levels of some ceramides, and their causative role in the disease has been widely assumed. In their model, however, the researchers observed that while ceramide levels were high in the bloodstream, levels in artery-lining endothelial cells remained about the same regardless of coronary artery disease status. This suggests that the current view of ceramides' role in the disease should be revised.

All in all, the findings lay the foundation for the development of drugs that boost S1P to treat or prevent coronary artery disease, the researchers concluded.

The work reported in this story was supported by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, through grant numbers R01HL126913 and R01HL152195 and a Harold S. Geneen Charitable Trust Award for Coronary Heart Disease Research.

Coronary Artery Disease

Coronary artery disease (CAD; also atherosclerotic heart disease) is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium (the muscle of the heart) with oxygen and nutrients. It is sometimes also called coronary heart disease (CHD). Although CAD is the most common cause of CHD, it is not the only one.

CAD is the leading cause of death worldwide. While the symptoms and signs of coronary artery disease are noted in the advanced state of disease, most individuals with coronary artery disease show no evidence of disease for decades as the disease progresses before the first onset of symptoms, often a "sudden" heart attack, finally arises. After decades of progression, some of these atheromatous plaques may rupture and (along with the activation of the blood clotting system) start limiting blood flow to the heart muscle. The disease is the most common cause of sudden death, and is also the most common reason for death of men and women over 20 years of age. According to present trends in the United States, half of healthy 40-year-old males will develop CAD in the future, and one in three healthy 40-year-old women. According to the Guinness Book of Records, Northern Ireland is the country with the most occurrences of CAD. By contrast, the Maasai of Africa have almost no heart disease.

As the degree of coronary artery disease progresses, there may be near-complete obstruction of the lumen of the coronary artery, severely restricting the flow of oxygen-carrying blood to the myocardium. Individuals with this degree of coronary artery disease typically have suffered from one or more myocardial infarctions (heart attacks), and may have signs and symptoms of chronic coronary ischemia, including symptoms of angina at rest and flash pulmonary edema.

A distinction should be made between myocardial ischemia and myocardial infarction. Ischemia means that the amount of blood supplied to the tissue is inadequate to supply the needs of the tissue. When the myocardium becomes ischemic, it does not function optimally. When large areas of the myocardium becomes ischemic, there can be impairment in the relaxation and contraction of the myocardium. If the blood flow to the tissue is improved, myocardial ischemia can be reversed. Infarction means that the tissue has undergone irreversible death due to lack of sufficient oxygen-rich blood.

An individual may develop a rupture of an atheromatous plaque at any stage of the spectrum of coronary artery disease. The acute rupture of a plaque may lead to an acute myocardial infarction (heart attack).

Inside A Coronary Bypass Surgery

Coronary artery disease, CAD, is a condition where the arteries that supply blood to the heart muscle become clogged and narrow, making it difficult for blood and oxygen to reach the muscles of the heart. Coronary bypass surgery is one treatment option to help restore blood flow, when other surgical procedures may not be recommended.

While coronary bypass surgery does not cure the underlying cause of CAD, it can alleviate symptoms, like chest pain, fatigue, difficulty breathing, and palpitations. It is done using general anesthesia, so you will be asleep during the entire procedure. Your surgeon will make an incision in your chest to access your heart and will use a machine to take over blood flow while your heart is temporarily stopped.

In some cases, minimally invasive procedures are possible, where smaller incisions are used or the heart does not need to be stopped. They will remove a healthy blood vessel from a different part of your body-- commonly from the lower leg, arm, or chest-- and relocate it to your heart. The healthy blood vessel will be attached to the heart above and below a blockage to allow blood to bypass the obstruction and flow more freely.

Once your surgeon confirms that blood is circulating properly, they will drain any fluids and sew the incision closed. Follow up with your doctor if you experience post-surgical complications, such as fever, any redness, pain, or discharge from the incision site. ","publisher":"WebMD Video"} ]]>

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Coronary artery disease, CAD, is a condition where the arteries that supply blood to the heart muscle become clogged and narrow, making it difficult for blood and oxygen to reach the muscles of the heart. Coronary bypass surgery is one treatment option to help restore blood flow, when other surgical procedures may not be recommended.

While coronary bypass surgery does not cure the underlying cause of CAD, it can alleviate symptoms, like chest pain, fatigue, difficulty breathing, and palpitations. It is done using general anesthesia, so you will be asleep during the entire procedure. Your surgeon will make an incision in your chest to access your heart and will use a machine to take over blood flow while your heart is temporarily stopped.

In some cases, minimally invasive procedures are possible, where smaller incisions are used or the heart does not need to be stopped. They will remove a healthy blood vessel from a different part of your body-- commonly from the lower leg, arm, or chest-- and relocate it to your heart. The healthy blood vessel will be attached to the heart above and below a blockage to allow blood to bypass the obstruction and flow more freely.

Once your surgeon confirms that blood is circulating properly, they will drain any fluids and sew the incision closed. Follow up with your doctor if you experience post-surgical complications, such as fever, any redness, pain, or discharge from the incision site.

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