Elevations in hs-cTnI Linked to Higher Risk of CVD, Particularly Heart Failure

Increased levels of plasma troponin I on a high-sensitivity assay are associated with an increased risk of cardiovascular events, particularly hospitalizations for heart failure, in a community-based sample of patients without preexisting cardiovascular disease, a new study shows.

When high-sensitivity cardiac troponin I (hs-cTnI) was added to the pooled risk cohort equation for atherosclerotic cardiovascular disease (ASCVD) risk assessment, there was a modest but statistically significant improvement in the prediction of cardiovascular events, including ASCVD and heart failure hospitalizations.

The results suggest that hs-cTnI could be used as a “pragmatic biomarker” in middle-aged and older adults for assessing global cardiovascular risk, given that elevations are a direct marker of injury to cardiac muscle, say researchers.

“Let’s say you have somebody who has hyperlipidemia and hypertension, not too bad, and they’re a little overweight,” senior investigator Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), told TCTMD. “Maybe they have impaired fasting glucose or diabetes that’s controlled. The real question is: do they have something going on with their heart muscle? When you’re measuring actual levels of troponin, what you’re seeing is if there are some changes in the end organ. We’re seeing subclinical injury.”

The study, which was published April 29, 2019, in Circulation, included 8,121 patients aged 54 to 74 years without baseline CVD who were participating in the Atherosclerosis Risk in Communities (ARIC) study. Using the new assay, manufactured by Abbott, detectable hs-cTnI was observed in 85% of the study population, with values ranging from 1.2 to 2575.4 ng/L. After a median follow-up of approximately 15 years, those with hs-cTnI levels in the lowest quintile had a significantly increased risk of incident CHD, ischemic stroke, ASCVD (CHD and stroke), heart failure hospitalization, global CVD (ASCVD and heart failure), and all-cause mortality when compared with those with the highest hs-cTnI levels (P for linearity < 0.001 for all endpoints).

hs-cTnI Quintile 5 (3.8 to 2575.4 ng/L) vs Quintile 1 (< 1.3 ng/L)

Although black individuals had higher overall hs-cTnI levels, in white patients there were stronger associations between hs-cTnI and ischemic stroke, heart failure hospitalizations, ASCVD, and global CVD. There was also an interaction by sex, with elevated hs-cTnI measurements carrying a greater risk of adverse events in women than in men. These differences, say investigators, might be driven by higher event rates at relatively lower hs-cTnI values in black participants and female subjects.

The researchers also reported that hs-cTnI and high-sensitivity cardiac troponin T (hs-cTnT) were only moderately correlated and complementary in predicting risk, with higher levels of both troponins associated with a higher risk of clinical events compared with elevation of a single protein alone. As noted, adding hs-cTnI to the pooled cohort equation improved risk prediction, as measured by the change in the area under the curve, for ASCVD and heart failure hospitalizations.

“High-sensitivity troponin is really going to be a major learning experience,” said Ballantyne. “First, we have the issue where in the ER they can make a diagnosis of ACS faster, but what’s happened in the past is you have cardiologists say, ‘Well, this person’s troponin didn’t go up and down so it’s not an MI.’ They’d say it’s a false-positive. Well, guess what? It’s not a false positive. People with chronic elevations in troponin have an increased risk for cardiovascular events.”

Some Challenges Still Remain

Allan Jaffe, MD (Mayo Clinic, Rochester, MN), who was not involved in the analysis, noted that several studies have emerged in recent years showing that cardiac troponin levels detected by high-sensitivity assays are robustly associated with CVD events in primary and secondary prevention populations. “It’s likely because troponin integrates across the entire spectrum,” said Jaffe. “It integrates the magnitude of underlying cardiovascular disease.”  

To TCTMD, Jaffe praised the study for several strengths, including the differentiation in risk among men and women, as well as by race, but noted that risk prediction at an individual-patient level still has some hurdles to clear. In the present study, he noted there is little separation of hs-cTnI values across the quintiles.

“If one takes into account the variability in the measurement, and the variability in the assays, then you could argue you can’t really tell in an individual patient the difference between a value in the first quintile and one in the fourth quintile,” said Jaffe. “As a matter of fact, at this very low end [of hs-cTnI levels], there is much more imprecision than there is at higher values. Add that to the fact that if you just leave a sample sit out on the table, seeing differences of 2, 3, or 4 [ng/L] is not uncommon. This becomes a very good technique in groups of patients but is much more difficult to use definitively in individual patients.”  

Quality assurances regarding the timing of the test and repeat testing of a sample could reduce imprecision, said Jaffe. Additionally, serial testing of hs-cTnI could track changes over time and thus mitigate imprecision at the individual level. “The marker is sensitive to our physical activity, and changes in our daily living,” said Jaffe. 

Ballantyne suggested that elevations in hs-cTnI in individuals without CVD are akin to a coronary artery calcium (CAC) score. While risk factors are important because they drive the disease process, the CAC score identifies damage to the artery, just as hs-cTnI identifies chronic, low-level damage to the myocardium.

“As you get older, the presence of some abnormality in the heart is more important than just having a risk factor,” said Ballantyne. “The pooled cohort equation is a risk equation for atherosclerotic cardiovascular disease, but it leaves out heart failure. If you take a look at what’s happening in the United States, the biggest emerging problem is heart failure, particularly in older people. . . I think we need to move beyond the pooled cohort equation and get into a global CVD equation and that’s where these biomarkers come in.”

James Januzzi, MD (Massachusetts General Hospital, Boston), who was not involved in the study, said that while the association of elevated hs-cTnI levels with a wide range of cardiovascular outcomes, including MI and heart failure, is not particularly new, he was surprised by the poor correlation between hs-cTnI and hs-cTnT. “In this regard, what is quite interesting is the additive value of the two troponins, suggesting they inform different pathophysiology,” he wrote in an email.