By AMERICAN HEART ASSOCIATION NEWS

Two recent studies highlight diverse but promising approaches, and a few potential pitfalls, in better preventing cardiovascular disease across broad populations.

One study focused on patients 75 and older in the Systolic Blood Pressure Intervention Trial, or SPRINT, a sweeping effort to discover whether heart disease and stroke rates could be reduced if blood pressure targets for hypertension were tightened beyond current standards. For patients in the tightly managed group, doctors aimed to reduce their systolic, or “top number,” reading to 120, instead of the typical target of 140. SPRINT found that the elderly patients with the lower target were about one-third less likely to have or die from a heart attack or stroke, or to die of any cause.

The other study linked mutations that inactivate the gene ANGPTL4 to a reduced risk of coronary artery disease. When active, the gene blocks an enzyme called lipoprotein lipase, or LPL. With the gene disabled, the enzyme was free to break down triglycerides, a fatty substance that, when elevated in the blood, may be associated with heart disease.

Together, the two studies were among the American Heart Association’s top 10 heart and stroke research advances for 2016 as important developments in cardiovascular disease prevention.

About three-quarters of Americans over 75 have high blood pressure. In the SPRINT study, published in the Journal of the American Medical Association, people in the tightly managed group achieved an average systolic reading of 123.4, compared with 134.8 in the other group.

With a rapidly growing elderly population in the U.S., the study raises the possibility that grave consequences of hypertension might be reduced, said lead study author Jeff Williamson, M.D. “Complications of hypertension are not only heart disease, stroke and death, but many of those complications lead to the loss of independence in older people,” he said.

Among people 75 and older, one patient would be spared a major cardiovascular problem for every 27 who were intensively treated for a median of about three years, while one person in 41 would be expected to avoid dying of any cause during that time, the researchers calculated.

“There are clear overall benefits in a very short time frame that this does reduce important endpoints,” said Donald Lloyd-Jones, M.D., chair of the Department of Preventive Medicine at Northwestern University Feinberg School of Medicine, who was not involved in the two studies. “The benefits seemed to be pretty universal. Even the more frail people were getting benefits at the same relative extent as the more robust people.”

Experts expect findings from the SPRINT study to be weighed as new guidelines, due this fall, are issued on high blood pressure care.

Risk of kidney damage was higher in the tightly managed group—5.5 percent of participants, compared with 4 percent in the comparison group. The kidney problems for the most part were quickly resolved, said Williamson, chief of Geriatric Medicine and Gerontology at Wake Forest University.

The other study, published in the New England Journal of Medicine, sequenced DNA from nearly 43,000 volunteers, largely of European ancestry, in Geisinger Health System’s DiscovEHR genetics research population. People with one or two copies of an ANGPTL4 mutation called E40K had lower levels of triglycerides, higher levels of the “good cholesterol” HDL, and were 19 percent less likely to have coronary artery disease, the study found. Also, people with any of 13 other newly identified mutations that inactivated that same gene had a 44 percent lower disease risk.

The work suggests addressing an LPL-related target might be a novel avenue to improve heart health, said lead author Rick Dewey, M.D., senior director of Translational Genetics at Regeneron Genetics Center in Tarrytown, New York. To identify the mutations, large numbers of subjects are needed.

“One of the primary reasons to embark on such large-scale sequencing … is to have the opportunity to discover these rare mutations that might have a protective effect and thereby point the way to drug targets that ultimately have benefit,” he said.

Regeneron Pharmaceuticals, collaborating with Geisinger, funds the DiscovEHR project, whose participants are part of a massive initiative that links patients’ biological samples with their electronic medical records.

While the research offers clear evidence that variations in ANGPTL4 are linked to lower levels of triglycerides, the study—as a snapshot in time of a specific population—can’t definitively show a downstream lowering of heart disease risk, Lloyd-Jones said.

“They’re building a case for that,” he said. “But until we intervene directly on this pathway we wouldn’t really know. Unfortunately the landscape is littered with highly promising targets that seem to be associated with lower coronary heart disease, but when you actually introduce a compound into the body, that’s not what happens.”

The Regeneron scientists also tested an experimental antibody in mice and monkeys that neutralizes the ANGPTL4 protein and found that the treatment could lower triglyceride and total cholesterol levels, mirroring the impact of the inactivated gene in humans and suggesting the protein might be a workable target for medications aimed at preventing cardiovascular disease.

Ultimately, the most substantial improvements in patients’ heart health are likely to rely on a big-picture approach to preventing cardiovascular illness, Lloyd-Jones believes.

“Because it’s a multifactorial disease, we really need to think about patients from the global perspective: what lifestyles are contributing to their risk, through their diabetes, smoking, etc.,” he said. “No one number, whether it’s blood pressure or triglycerides, can totally encompass cardiovascular disease risk.”

Editor’s note: This is one in a 10-part series of the top medical research advances of 2016 as determined by the American Heart Association.