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Two new studies provide more evidence in favor of triglycerides playing a causative role in cardiovascular disease. But it is still too early to know whether the findings of any of the studies will point to useful new methods to prevent and treat disease.

Two new studies provide more evidence tilting the balance in favor of triglycerides, rather than HDL, playing a causative role in cardiovascular disease. But it is still too early to know whether the findings of any of the studies will point to useful new methods to prevent and treat disease.

In the first study, , researchers in Israel analyzed 22-year follow-up data from more than 15,000 patients who had been screened for the Bezafibrate Infarction Prevention (BIP) trial. They found a significant and independent association between triglyceride levels and mortality. At 22 years, the survival rate for people with triglyceride levels over 500 mg/dL was significantly lower when compared to people with triglyceride levels below 100 mg/dL (25% versus 41%).

In an , Karol Watson, MD, PhD, and Philipp Wiesner, MD, wrote that the study "adds to our scientific knowledge about the potential role of elevated triglycerides in cardiovascular risk, especially given the large numbers of individuals studied and the long follow-up."

But, they pointed out, BIP was performed in the era before widespread use of statins. It is unclear whether the findings would be the same in a contemporary population. While it is known that there is significant residual risk in people taking statins who still have elevated triglycerides, outcomes trials with drugs that lower triglycerides have not demonstrated benefit.

"The results of these outcome trials fail to support the hypothesis that a triglyceride-lowering drug reduces the risk for cardiovascular events among statin-treated patients -- or at least the drugs that were studied in those trials," wrote the editorialists. "We must always remember that simply because something may or may not be a cardiovascular risk factor, altering it pharmacologically does not always mean that we will lower risk," they concluded.

In the second new study, , researchers identified a rare genetic variation in an HDL receptor gene that leads to increased levels of HDL in the blood. Although carriers have elevated HDL levels, they have an increased risk for heart disease.

That finding runs counter to expectations raised by several generations of epidemiology studies consistently finding that HDL is inversely correlated with heart disease -- though studies with drugs that raise HDL have not been successful.

Study co-author , of the Broad Institute in Cambridge, Mass, who has led previous genetic studies that found a causal role for triglycerides, admited that the new study does not rule out “an alternative HDL hypothesis emerging now that what really matters is HDL functionality.” However, he cautions that “this is a new hypothesis that requires evidence.”

This is "another nail in coffin for the simple notion that anything that raises HDL must be good for you," said study co-author , of the Broad Institute in Cambridge, Mass. But Kathiresan, who has led previous genetic studies that found a causal role for triglycerides, admited that the new study does not rule out "an alternative HDL hypothesis emerging now that what really matters is HDL functionality." However, he cautions that "this is a new hypothesis that requires evidence."

The Science study examined the effect of a gene variant of scavenger receptor BI (SR-BI) gene, the first identified HDL receptor. The rare variant appears to prevent cells from absorbing HDL cholesterol, thereby leaving more circulating HDL cholesterol in the blood.

, of MIT, who discovered SR-BI more than 20 years ago, agreed with Kathiresan that the study is "another case where the most simple model of the HDL hypothesis (HDL cholesterol itself is atheroprotective) does not hold." Krieger also agreed that the study does not rule out alternative mechanisms of action involving HDL's functional role in reverse cholesterol transport. Krieger and others also have suggested that SR-BI may have a functional role that is not dependent on the level of circulating HDL in the blood.

Regarding triglycerides, Kathiresan also emphasized the distinction between plasma triglycerides and pointed out that the latest genetic studies suggest that plasma triglycerides may be less important than triglyceride-rich lipoproteins (TRLs). Recent genetic studies performed by Kathiresan and others, including , have identified TRL-regulating genes that appear to have a direct causal role in heart disease.

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