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Non-laboratory tests may predict CVD risk as effectively as lab-based tests.

News from the Harvard Medical School research community.

Cardiovascular medicine

Simple non-laboratory methods as good as laboratory tests at predicting cardiovascular disease risk

In a new study from Brigham and Women's Hospital (BWH), researchers show that methods using non-laboratory-based risk factors predict cardiovascular events as accurately as more costly laboratory-based tests. These results are published in the March 14, 2008 issue of Lancet.

"Using non-laboratory tests could simplify risk assessment in countries where laboratory testing is inconvenient or unavailable," said Thomas Gaziano, MD of the Division of Cardiovascular Medicine at BWH and lead author of the study.

Using a previous cohort developed in the early 1970s and comprised of 14,407 US participants between the ages of 25 -74, Gaziano and colleagues re-analysed the NHANES I study.

The follow-up study population included 6186 participants who did not report a history of cardiovascular disease (heart attack, heart failure, stroke, angina), or cancer.

The lab-based method, which required blood-tests, looked at age, systolic blood pressure, smoking status, total cholesterol, reported diabetes status, and current treatment for high blood pressure. The non-lab method substituted body-mass index for cholesterol.

Researchers found that in the 6186 people initially not reporting a history of CVD, there were 1529 first-time cardiovascular events and 578 deaths due to cardiovascular disease over a 21 year period.

Both lab and non-lab methods calculated a number called the c-statistic to assess cardiovascular risk prediction, and for both men and women, lab and non-lab methods gave similar c-statistics.

Furthermore, the non-lab method correctly classified patients at the same rate as the lab method across four commonly used levels of risk used in guidelines around the world, suggesting good calibration.

Study authors add that the cost for developing nations to perform cholesterol tests on patients who were at risk for the development of cardiovascular disease could use more than 10 percent of the nation's health care budget, which adds little benefit to non-lab tests.

Non-lab test are effective at collecting the appropriate information to determine risk quickly and in a non-invasive way.

"Approximately 80 percent of cardiovascular deaths occur in developing countries where assessment of patients at high risk is an important strategy for prevention. Since developing countries have limited resources for laboratory testing, cheap, simple and effective, non-lab methods of testing would help immensely," said Gaziano.

Cancer treatment

Regulator of microRNAs is key to cell reprogramming and carcinogenesis: Could provide target for enhancing stem-cell generation or inhibiting cancer

MicroRNAs are a recently discovered class of RNAs that encode no proteins but instead regulate gene activity. Researchers at Children's Hospital Boston and the Harvard Stem Cell Institute have discovered the first protein to block the processing of immature microRNAs in cells to mature forms.

Drugs that target this protein, known as Lin-28, have the potential to influence the creation of stem cells and provide a new approach to treating some cancers, the authors say.

The discovery, reported online February 21 in ScienceExpress, "provides a key insight into two fundamental processes in biology--stem cell generation and carcinogenesis," says Richard Gregory, PhD, the study's senior author.

Lin-28 regulates the let-7 family of microRNAs, known to be key players in cancers of the lung and breast, and was also recently shown to help reprogram skin cells to pluripotent stem cells resembling embryonic stem cells.

Because both cellular reprogramming and carcinogenesis entail cellular de-differentiation (reversion of a mature cell to a less mature state), Lin-28 provides a missing link between stem cell generation and cancer.

"We are actively seeking drugs that mimic or block the effect of Lin-28 on microRNAs, as these drugs will either enhance stem cell generation, or inhibit cancers, respectively," says Gregory.

In 2006, Scott Hammond's group at University of North Carolina, Chapel Hill, discovered that microRNAs were made as immature forms in embryonic cells and cancer cells, but the mechanism for the blocking of their maturation remained elusive.

Srini Viswanathan, a graduate student in the laboratory of George Daley, MD, PhD, at Children's Hospital Boston, was interested in how microRNAs might dictate tissue formation from embryonic stem cells, which show a block in processing of a specific family of microRNAs called let-7.

Viswanathan and Gregory hypothesized that some protein must bind to the immature form of let-7 microRNAs to block their processing, and set out to purify the protein. They identified a number of proteins associated with microRNAs, but only Lin-28 was uniquely expressed in embryonic tissues.

They then demonstrated that Lin-28 was directly responsible for the blockade of let-7 microRNA in embryonic cells: expressing Lin-28 in non-embryonic cells reproduced the block in let-7 processing, and inhibiting Lin-28 expression in embryonic tissues caused upregulation of let-7.

Unbeknownst to the Children's researchers, Lin-28 was being studied by James Thomson's group at the University of Wisconsin as a factor that enhanced reprogramming of skin cells back to an embryonic state.

Thomson's paper (published while the Children's paper was under review) did not provide an explanation for how Lin-28 could contribute to stem cell generation. "Our study helps explain how Lin-28 works--by blocking microRNAs that promote cell differentiation," says Daley.

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