Six promising cardiac microRNAs failed to show sufficient diagnostic or prognostic potential in distinguishing between unstable angina and myocardial infarction, according to a study by researchers at Hannover Medical School in Germany.
The team, led by Kai Wollert and Thomas Thum, tested six miRNAs previously proposed as potential diagnostic markers in acute coronary syndrome. They evaluated the miRNAs’ ability to discern between myocardial infarction and unstable angina, as well as their ability to predict prognosis in a cohort of 444 ACS patients.
The results appeared in the online edition of the Journal of Molecular and Cellular Cardiology.
Wollert told Gene Silencing News that previous studies have suggested circulating miRNAs might be a good source of diagnostic and prognostic information in ACS. Other groups have shown the six miRNAs the team evaluated can successfully distinguish between patients with an MI and healthy controls, but none have established a prognostic signature, the authors wrote.
"There have been actually probably eight or ten publications where … the miRNAs, or at least some of those cardiac restricted miRNAs, were very much elevated in patients with myocardial infarction compared to healthy controls or [those with] stable coronary artery disease,” he said.
“But there was no information on prognosis or whether the levels are increased in comparison to a patient with unstable angina,” he noted.
Unstable angina, severe chest pain caused by disruption of an atherosclerotic plaque, is considered a subset of ACS along with myocardial infarction, Wollert said.
In their study, Wollert and his colleagues measured the concentrations of miR-1, miR-133a, miR-133b, miR-208a, miR-208b, and miR-499 in plasma samples obtained on admission from their 444 patient cohort using quantitative reverse transcription PCR. Patients were followed for six months for mortality by any cause.
In the group’s results, three of the miRNAs were differentially expressed in the two different conditions: patients with NSTEMI or STEMI presented with higher levels of miR-1, miR133a, and miR-208b compared with patients with unstable angina. However, the overlap between the miRNAs in each condition was too high for the signature to serve as a reliable diagnostic, said Wollert.
‘What we show here is that these [heart-associated] miRNAs … surprisingly, none of these biomarkers can really distinguish a situation where you have myocardial infarction or you have only unstable angina,” Wollert said.
“It’s easier to show that the miRNAs can distinguish between a 70 year old patient with myocardial infarction and a healthy 20 year old medical student — and that's essentially what the previous studies did — but it’s more clinically relevant that you distinguish two 70 years olds that have come to the ER, one with a myocardial infarction, the other with unstable angina,” he said.
“Based on this overlap we observe, they are absolutely not useful to make this distinction.”
In prognosis, the signature also performed poorly, which Wollert called “disappointing.”
Out of the six miRNAs the team investigated, two — miR-133a and miR-208b — showed prognostic association in univariate and age/gender adjusted analyses.
“Patients with higher miRNA levels, they have higher mortality,” a result that provides “some prognostic information, and this is even still present when you adjust for age and gender,” Wollert noted.
The authors wrote that their study is “the first to show that miRNAs can provide prognostic information in ACS.”
However, this prognostic power didn’t remain after adjusting for levels of high-sensitivity troponin T, a protein maker considered the gold standard in distinguishing between MI and unstable angina.
“Out of six miRNAs none of them added prognostic information to troponin,” said Wollert.
“I think that's quite significant information. It’s negative information, but actually they were performing quite poorly as biomarkers,” he said.
According to Wollert, troponin is the main distinguishing criterion for the different types of acute coronary syndrome. Overall, the six miRNAs didn’t add any prognostic ability to troponin alone, and didn’t show enough differentiation between MI and unstable angina to challenge the diagnostic power of the protein, the authors report, suggesting there is little potential for their use as a prognostic or diagnostic assay.
But, he said, the team can’t rule out the possibility that additional miRNAs might make a more powerful signature or that measuring their levels at different points in patients’ disease progression might improve their prognostic, though not likely their diagnostic, performance.
The researchers only measured miRNA levels upon subjects’ admission to the hospital. In their paper, the authors wrote that “It remains possible that measurement of miRNAs at later time points enhances their prognostic value.” Wollert said serial sampling over the course of a patient's hospitalization might catch the miRNAs when elevated to a point where they offer a stronger prognostic link.
Wollert said the results were negative enough that the team doesn’t plan to continue work in this vein. “Based on these data, I didn't even bother to talk to the patent people here at the medical school,” he said.
The researchers conclude in their paper that the study should temper “speculations about the potential usefulness of miR-1, miR-133a, miR-133b, miR-208, miR-208b, and miR-499 as diagnostic or prognostic markers in ACS.”
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