Physicians trying to get to the heart—and gut—of the relationship between heart failure and intestinal flora found that higher levels of microbe metabolites in the blood stream appeared to predict mortality risk. Heart failure patients stratified by levels of trimethylamine-N-oxide (TMAO) found in blood samples had progressively more risk for death by year five.

The Cleveland-based research team previously worked with TMAO in heart disease and noted a link between high levels of TMAO and increased risk for stroke, heart attack or death. TMAO is the oxidized product of gut bacteria that have consumed l-carnitine or lecithin from red meat, eggs or energy supplements.

The findings were put forth as further evidence of the so-called "gut hypothesis," linking translocation of gut flora to poorer outcomes in heart failure patients. 

W. H. Wilson Tang, MD, of the Cleveland Clinic, and colleagues enrolled two cohorts: stable cardiac disease patients and healthy volunteers. Heart failure patients were prospectively enrolled between 2001 and 2007 through the Cleveland Clinic. Fasting blood samples were collected and reviewed for TMAO, B-type natriuretic peptide (BNP), C-reactive protein and other biomarkers. Patients were followed for five years.

Between the heart failure and healthy cohorts, median TMAO was 2.5 µM higher in patients with heart failure at baseline. Within the heart failure cohort, four TMAO level quartiles emerged. The highest-risk patients had the highest levels of TMAO (hazard ratio: 3.42) when compared to those with lowest levels of TMAO and heart failure with an increased risk continuing through five years after adjustment for traditional risks (hazard ratio: 1.18). Mortality risks remained regardless of ischemia.

Patients with elevated fasting TMAO had 2.2-times greater risk after adjustment for BNP and other factors. With BNP factored in, however, patients with the highest TMAO and high levels of BNP had 5.7-fold higher mortality risk compared with patients with low levels of both. Yet, in patients with high levels of BNP but low levels of TMAO, risk for mortality was far lower than patients who had high levels of both.

While TMAO is generally eliminated in the urine of healthy individuals, Tang et al suggested that worsening conditions and kidney impairment may be keeping TMAO from being adequately eliminated through low estimated glomerular filtration rate.

In a press release, co-author Stanley Hazen, MD, PhD, of the Cleveland Clinic said, “I’m excited that these studies suggest TMAO testing may not only help identify those patients at greatest risk and for whom more aggressive monitoring is needed, but also that of TMAO testing may help to tailor dietary efforts to the individual in hopes of reducing future risks among those high-risk subjects.”

Tang et al suggested that future interventions that targeted alteration of gut microbiota might be warranted.

This study was published in the Nov. 4 issue of the Journal of the American College of Cardiology.