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Specific microRNAs Linked to Post-MI Remodeling

Key findings

  • Extracellular small non-coding RNAs have been associated with cardiac inflammation and fibrosis and may be associated with left ventricular (LV) remodeling after myocardial infarction
  • This exploratory study showed an association between different groups of microRNAs and specific features of LV remodeling, as evaluated by cardiac MRI in the subacute post-MI phase
  • The association of microRNAs with LV remodeling phenotypes suggests they may have a role in the molecular processes that produce remodeling

After myocardial infarction, left ventricular (LV) remodeling can be beneficial, as inflammation removes dead cardiomyocytes and begins the repair process. However, if inflammation fails to resolve, it produces molecular changes that can lead to heart failure. Thus, early identification of pathological remodeling is an important challenge in treating MI patients.

Natriuretic peptides, the current standard biomarker for heart failure, are typically elevated only after substantial remodeling has already occurred. Therefore, researchers are searching for earlier markers of adverse LV remodeling and therapeutic targets that can prevent post-MI heart failure.

In EBioMedicine, a team headed by Saumya Das, MD, PhD, co-director of Resynchronization and Advanced Cardiac Therapeutics Program, with co-investigators Ravi Shah, MD, Anthony Rosenzweig, MD, chief of Cardiology from Mass General and Raymond Kwong, MD, MPH from Brigham and Women’s Hospital, reports early progress towards that goal. The team found that in the subacute post-MI phase, certain microRNAs are associated with certain measures of LV remodeling, including those related to myocardial extracellular matrix expansion and hypertrophy.

The conclusion comes from an analysis of data from the OMEGA-REMODEL trial, which evaluated how omega-3 fatty acid supplementation after acute MI affects LV remodeling. As part of that trial, 331 patients had blood samples collected two to four weeks post-MI. A total of 238 patients also underwent post-treatment follow-up with serial cardiac MRI. The measurements included LV end systolic volume index (LVESVI), LV ejection fraction (LVEF), myocardial mass, infarct size and extracellular volume fraction, a validated surrogate measure of myocardial interstitial expansion.

Beneficial LV remodeling was defined as >20% reduction of the LVESVI, which is known to be highly specific for a favorable post-MI prognosis. Adverse remodeling was defined as expansion of the LVESVI by >15%.

The researchers matched patients who showed beneficial remodeling and those who showed adverse remodeling according to baseline demographics and disease severity. They performed RNA sequencing on blood samples from the 11 best-matched pairs and found 21 microRNA candidates that were differentially expressed between patients with beneficial versus adverse remodeling.

For the validation phase of the study, the researchers added those 21 microRNAs to 12 microRNAs previously reported to be relevant to cardiovascular disease. Using quantitative reverse transcription polymerase chain reaction, they measured those microRNAs in blood samples from all 331 patients, then examined the results using principal components regression analysis.

That method allowed the researchers to examine correlations between distinct sets of microRNA and specific features of LV remodeling on MRI. 14 microRNAs were significantly associated with changes in LV mass: LVESVI, LVEF and LV mass, and/or extracellular volume fraction.

The researchers then looked at which messenger RNAs are targets of those 14 microRNAs. That analysis predicted they may be functionally implicated in cellular pathways relevant to LV remodeling, including apoptosis signaling, inflammatory signaling and fibrotic pathways.

The relationship with inflammatory signaling particularly interested the research team, because each principal component was related to nuclear factor κB signaling, which leads to increased interleukin-1β activity. Anakinra, which has been shown to reduce adverse post-MI remodeling and decrease the risk of heart failure hospitalization, is an interleukin-1β pathway antagonist.

The authors emphasize that it was not their goal to identify a definitive marker for predicting adverse LV remodeling after MI. Rather, their findings are important because they provide insight into the processes that drive adverse versus beneficial remodeling. These insights can be used to study whether specific microRNAs exert their effect on post-MI remodeling through the IL-1β pathway and whether changes in those microRNAs in response to anti-inflammatory therapy might serve as novel biomarkers of response.

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