Researchers are really closing in on the molecular factors behind heart failure, and this week brought two interesting bits of news in that area. In epigenetic research, the University of Cambridge’s Dr. Roger Foo and colleagues published what seems to be the very first epigenome-wide association study comparing normal hearts to failed hearts, finding among other things that in cells of failed hearts, there seems to be more CpG methylation in intragenic regions, while upregulated genes show lower CpG-island methylation. And just a week before, researchers at the Massachusetts General Hospital Heart Center published results from the PROTECT study, which took a close look at whether it’s useful for doctors to use chaning levels of the protein NT-proBNP to guide treatment of heart failure patients.
The two aren’t directly related, but they form pieces of the same puzzle. For the last ten years or so, heart researchers have gradually established NT-proBNP as a useful biomarker to distinguish heart failure patients from lung disease patients, and later to show that it’s useful for guiding patient prognosis and for identifying patients who need more intensive care. The Mass General group’s PROTECT study goes even further by showing that patients have fewer adverse events when doctors keep NT-proBNP levels below 1ng/mL with particular drugs at specific dosages–and the trial was so successful that the researchers halted it early.
Here’s where the epigenomics might play a role. The gene encoding NT-proBNP is one of many that cardiac cells upregulate in failed hearts. For at least a decade, researchers have been developing gene expression profiles of heart failure (here’s an important study here), but no one really understands the mechanics behind that–transcription factor binding and so forth obviously play a role, but those processes are probably not the only ones.
The research from Cambridge’s Roger Foo and colleagues are consistent with the idea that epigenetics could be behind some of those heart-failure gene expression changes, though when I spoke to him yesterday, he was hesitant to draw that conclusion outright, particularly for the famous heart-failure biomarker. “It could be hypothesized that an epigenetic process drives the NT-proBNP upregulation, but there’s no way we’ll be able to say ‘for sure’ for a long time,” he said.
Like a lot of work in epigenetics, Foo and colleagues’ study is mostly an effort to get the lay of the land. “My biggest motivation for this work was to step into the circle,” he says. “To understand whether there are any differences between a normal heart and a diseased heart. We’re just really trying to describe what’s going on, and to be perfectly honest, it’s still not clear what’s going on.”
But so far, so good. “What’s impressive is that these diffs are robust and clear, even in this small sample size,” says Foo. And the sample size is quite small, to be sure, with tissue from four failed hearts and four normal hearts. In brief, the group found less overall CpG island methylation near promoters of genes that’re upregulated during heart failure, while genes in failed hearts contained more methylation overall within genes. They add:
“This study is also consistent with our previous report in which we used a different series of hearts and a different assay and found that large numbers of CGIs and gene promoters were significantly more hypomethylated in human cardiomyopathy.”
There’s another aspect of this research that’s new. “We looked at profiles of histone modification and found that some parts of the genome had [differential] histone profiles, even though they’re not near genes. They’re being transcribed,” says Foo. “We’ve also shown that there’s a lot of non-coding RNA that people don’t know about yet. So it opens a whole new avenue that people can go and search down. One of these upregulated RNAs is DUX4, which is associated with a hereditary myopathic disorder and is drawing increasing attention in heart research.
Foo says it’s not realistic to turn their findings into an epigenetic diagnostic of any kind–at least not until someone finds that related, detectable changes occur in the blood. But when his group and other researchers can flesh out more of the epigenetics of heart failure, that work will probably yield useful drug targets.
The investigators’ next step will probably involve taking a look at the effects of drugs and genetic tricks to cause heart failure phenotype through epigenetic changes in animal models, says Foo. “There I think you might be able to see more of a cause and effect relationship.”
Interestingly, the much more advanced field of cancer epigenetics has created an opening in that area. “We know that some of these cancer epigenome-targeting drugs can cause heart failure as a side-effect,” he says. “So you could be treating someone of cancer and give him heart failure.”
He’s also spoken to BLUEPRINT’s Henk Stunnenberg about looking deeper into heart-related epigenetics, but so far there aren’t any concrete plans.
[The picture "Heart on Union Square" by Flickr user Phillie Casablanca is reproduced here under a Creative Commons license.]
Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T, Siggens L, Vujic A, Simeoni I, Penkett C, Goddard M, Lio P, Bennett MR, & Foo RS (2011). Distinct Epigenomic Features in End-Stage Failing Human Hearts. Circulation PMID: 22025602