TnT could be a dynamite CHF marker, but experts disagree over usefulness
TnT could be a dynamite CHF marker, but experts disagree over usefulness
Questions about specificity linger despite researchers’ optimistic report
Two European investigators report the protein troponin T (TnT) may be a likely candidate in the search for a biochemical signal for CHF.1
As a chemical marker, TnT looks promising. Its levels rise with the worsening of CHF symptoms. It’s easy to measure, like its relative troponin I, which doctors already use as a chemical marker for acute myocardial infarction. But the researchers note that monitoring levels of TnT can indicate more than myocardial injury: It can be used clinically to monitor CHF and to detect left ventricular dysfunction and ongoing heart muscle damage.
Most clinicians agree that it would be helpful to identify patients who seem to be showing the early signs of CHF. But today’s diagnostic methods often are not sensitive enough to identify those at risk, especially those with asymptomatic left ventricular dysfunction.
Clinicians frequently express a need for a sensitive and specific biochemical test that would properly detect subclinical myocardial injury before signs of overt failure occur. The European group concluded cardiac TnT concentration may fit the bill. It rises in CHF patients and suggests a simple way to identify suspected heart failure by measuring this marker protein and monitoring the effect of treatment.
In their study, increases in the creatine kinase isoenzyme (CK-MB) also paralleled the severity of the disease, and both indicators correlated with the decline of left ventricular function. Markers of injury were equally distributed across patients with idiopathic dilated cardiomyopathy and ischemic cardiomyopathy with a clear (although statistically nonsignificant) increase in the dilated cardiomyopathy group.
The French and Austrian investigators looked at plasma samples from 33 CHF patients and 47 healthy controls. All 33 were in stable clinical condition; they had not had recent medication changes and had no signs of worsening heart failure requiring IV inotropic or inodilator therapy.
These factors excluded candidates from the study: acute myocardial infarction, unstable angina, cardiac surgery, chronic or acutely decompensated pulmonary disease, end-stage renal failure, severe systemic illness, or skeletal muscle diseases. The participants received standard therapy, including digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors.
To evaluate the relation between plasma cardiac TnT and severity of CHF, patients were categorized according to the level of their functional impairment:
- those with asymptomatic to mild heart failure, NYHA class I-II, left ventricular ejection fraction (LVEF) > 45%;
- those with more advanced disease, NYHA class III-IV, LVEF = 45%.
One-third of the patients were in class I-II, and the rest exhibited NYHA class III-IV symptoms. A little more than half had a diagnosis of CHF caused by ischemic heart disease. Idiopathic dilated cardiomyopathy was diagnosed in the rest of the group.
The control population was composed of age- and sex-matched healthy blood donors without evidence of cardiovascular or any other disease.
Concentrations of cardiac TnT was significantly higher in the group of patients with CHF than in control subjects, and that the higher levels paralleled the severity of the patients’ disease. Patients with moderate to severe CHF had mean cardiac TnT plasma concentrations significantly higher than patients in class I-II. The mean circulating level of TnT was 0.140 ± 0.439 ng/mL in patients with heart failure and 0.0002 ± 0.001 ng/mL in the healthy controls. (See chart showing levels, p. 123.)
Mean levels of CK-MB were also increased in patients with heart failure, and there were clear increases of both TnT and CK-MB in the dilated cardiomyopathy group. (The highest values of TnT, 0.84 and 2.32 ng/mL, were measured in those patients.) Two patients with idiopathic dilated cardiomyopathy had CK-MB levels of 6.5 and 20.7 ng/mL, and one patient with ischemic cardiomyopathy registered 8.2 ng/mL. CHF patients were also sectioned off according to their LVEF so the relation between structural degradation and functional impairment could be evaluated. A negative correlation was found between plasma concentration of cardiac TnT and LVEF.
Observers respond
"I don’t know that TnT has enough specificity yet to act as a diagnostic marker for heart failure," says Douglas Mann, MD, chief of cardiology at Houston’s VA Medical Center and professor of medicine at Baylor University, also in Houston. "The enzyme is important pathophysiologically because it tells us ongoing necrosis is likely, and that is important for understanding disease progression. But I’m not 100% certain that you can reliably use that level to pick out a patient with or without CHF. For example, levels are elevated in myocardial ischemia and in unstable angina, and those patients might not have CHF."
Mann adds that while TnT is a specific indicator for muscle damage, there are a lot of events that cause muscle damage. Future researchers will need to study larger groups of people over longer periods of time to come to a positive conclusion, he explains. They will have to study diverse populations with different kinds of cardiac problems. "Future researchers need to be able to establish whether there’s a reliable cutoff. In other words, if TnT is elevated above X,’ does that clearly mean you’re looking at heart failure?"
At Boston University School of Medicine, researchers are using troponins when looking at how different parts of the heart failure disease process correlate with myocardial remodeling, including myocyte death by apoptosis, says Douglas B. Sawyer, MD, assistant professor in the department of medicine. "Here, the enzyme is more of a research tool than a clinical tool, but it could become a clinical tool, if we find that it responds to therapy." For example, he explains, if a patient comes into the office with high troponin levels, and you put him on a set of drugs helpful in heart failure and his troponin levels go down, that would be useful information. "Such an indicator might be more sensitive than trying to find a change in a patient’s cardiac function by echocardiogram." But he says screening patients with troponins for heart failure is problematic.
"It’s more useful as a marker for ongoing disease," says Sawyer. Troponin in the serum of patients with CHF does have value prognostically as it correlates with heart function. But shifts in the expression of troponin that occur in CHF may have more to do with contractile dysfunction and ongoing myocyte death than disease progression. "The use of the marker is not straightforward," he adds. "It does not necessarily have any benefit as a measuring component in an ambulatory patient, but it might be useful in determining response to therapy."
Charles E. Rackley, MD, a cardiologist at Georgetown University in Washington, DC, agrees with Sawyer and says that troponin is such a sensitive enzyme, it raises the possibility of myocardial damage — underlying ischemia and/or necrosis of heart muscle — rather than heart failure per se. "I have a major reservation about using this highly sensitive enzyme as a marker for CHF," says Rackley. "TnT is generally considered evidence of myocardial necrosis or a small myocardial infarction. The data presented in the study could be interpreted a little differently, rather than saying TnT is a marker for HF."
Troponin enzyme assay is primarily used for detection of myocardial necrosis, which is the definition of a heart attack, he continues. "If a patient with heart failure has a rise in troponin, most everyone would consider this evidence of damage to the heart muscle in terms of a heart attack, and the patient would be treated as a heart attack candidate. Most would not consider it a cue to chemically monitor his heart failure. This may be a misleading interpretation of the data."
The first interpretation of an elevation of troponin would be that the patient had a small infarction, which would explain the worsening of the CHF. "If he’s had an infarction and has CHF," Rackley continues, "that does increase the complexity of his prognosis in terms of morbidity and mortality." The enzyme elevation would be a chemical reflection of heart muscle damage rather than just mere weakening of the heart muscle itself. And that is the distinction between infarction and CHF; in CHF the heart muscle gets weak. "But the question is: What is weakening it?" he says. "If it’s been damaged and releases troponin, it surely would indicate that the CHF is getting worse, not the reason it’s getting worse. The patient is having a heart attack."
Randall Williams, MD, a cardiologist at the CHF program at Evanston (IL) Hospital, says that 60% or more of patients with CHF have ischemic coronary artery disease. "It’s likely, therefore, that troponin abnormalities will be present in patients with CHF due not to their heart failure, but due to their coronary disease. It’s also known that heart muscle enzymes can change in both relative proportion and in specific amounts in patients with hypertensive disease." Since hypertension is the No. 1 risk factor for developing CHF, in both that scenario and that of ischemic coronary artery disease, troponin may already be abnormal. "It’s probably more important to recognize a change in troponin rather than a simple elevation in terms of using the information for prognosis. Levels could go up or down. Even stable patients with CHF don’t have troponin levels in a normal reference range," he adds.
Reference
1. Missov E, Mair J. A novel biochemical approach to congestive heart failure: Cardiac troponin T. Am Heart J 1999; 138(1):95-99.
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