Come and listen to a story about a blood test named HDL (High Density Lipoprotein, the “good cholesterol”). It is an epic saga full of lows and highs. It is a story that spans the globe, from Massachusetts to the Italian Alps. What is HDL and how is it associated with heart disease?
The story begins in a town outside of Boston, Massachusetts. In 1977, the famous Framingham Heart Study first identified low levels of HDL in the blood as a risk factor for heart artery disease. In patients with HDL levels less than 40 mg/dl, there is an increased risk for blockage in the heart arteries and cardiac death. On the other hand, in patients with elevated LDL (the “bad cholesterol”) normal or high levels of HDL protect against heart disease. The prevalence of low HDL in North America is about 7% in men and 2% in women. How does HDL protect against plaque build up in arteries? There are several mechanisms. HDL transports excess cholesterol from arteries back to the liver, where it is metabolized and excreted. This process is called reverse cholesterol transfer. In effect, HDL “cleans” the arterial wall, sweeping away cholesterol and stopping plaque in its track. In addition, HDL is anti-inflammatory (plaque formation is an inflammatory disease) and has anti-oxidant and anti-blood clotting properties. Are there ways to treat low HDL? Aerobic exercise, weight loss and smoking cessation all increase HDL levels. Diet plays a role as well. Low fat diets lower both LDL and HDL levels but diets high in monounsaturated fats (including olive oil) reduce LDL without adversely affecting HDL. Statins will increase HDL levels. They raise HDL between 5% and 15% with an average increase of 9%. Many, many other pharmacologic agents have been tried to see if they can raise HDL levels and improve outcomes. Niacin and fenofibrate both raise HDL (by concomitantly lowering triglycerides). However, despite the positive impact on HDL levels, both drugs failed to reduce heart attacks, strokes and cardiac deaths. Several other medications have been tried, but in clinical trials they all failed to improve cardiac events, some agents even raised mortality. There are several reasons for the failure of theses medications. The biology of HDL appears to be much more complex than that of LDL. There are several different subclasses of HDL; we don’t know which ones are the keys to the success of HDL. In addition, the function of the HDL molecule is more important than the level. Increasing the amount of HDL doesn’t mean it works better at preventing artery blockage.
At this point, the story of HDL heads overseas to two small towns in Italy. In 1980, a genetic mutation in HDL was discovered in families in a town outside of Milan. People with this mutation were smokers, did not follow a heart healthy diet, and had low levels of HDL (10 to 30 mg/dl). Yet they had low levels of blockage in the heart arteries and lived well into their 90’s. Researchers discovered that their genetic mutation (called apolipoprotein A-1 Milano) was protective against heart disease. Subsequent trials tested whether IV infusions of this apolipoprotein could help patients with established heart disease, but again the trials failed. In another town, this one located in the Italian Alps, there is a cohort of people who have longevity and virtually no heart disease. Like their countrymen, their diet is not heart healthy but they have higher levels of HDL than the average Italian. The genetic variant in this healthy town has not yet been identified.
The guidelines for lipid management recommend a threshold value for HDL of 40 mg/dl; below that level there is an increased risk for heart disease while levels above provide protection. If an HDL value of 40 mg/dl is good, is 100 mg/dl better? Does the risk for heart disease continue to fall as HDL levels rise? How high is too high? To answer the question researchers pooled multiple studies of HDL (all told more than a million patients were evaluated). They found a U shaped relationship between HDL levels and death. Levels below 40 mg/dl were associated with increased risk of death. Surprisingly, levels over 80 mg/dl also were associated with increased deaths. They found the optimal range of HDL to be between 40 and 80 mg/dl.
The final chapter to the HDL saga has not yet been written. If you are not genetically gifted and have a low HDL level, do what you can to raise HDL. Stay active, exercise, keep weight down, don’t smoke and take your statin. If you have a very high HDL level, don’t assume that you are protected against heart disease. A healthy lifestyle and a statin may still be necessary if the LDL level is also elevated. Only time and further research will tell whether there is a better approach to HDL and a happy ending to the story.
