A collaborative study by researchers from Massachusetts General Hospital (MGH) and the University Hospital of Maastricht, The Netherlands, has identified a new candidate biomarker for heart failure with the potential of further improving the challenging task of diagnosing and predicting outcomes for patients with symptoms of heart failure, primarily shortness of breath. In the September 19 Journal of the American College of Cardiology, the investigators report that elevated blood levels of galectin-3, an inflammatory protein, can help diagnose heart failure and identify patients at risk of dying within 60 days. Another potential marker, apelin, did not prove to be useful.
"Heart failure is one of the most difficult diagnoses to make accurately, since it has numerous, varied symptoms, and signs that indicate heart failure are hard to detect," says James Januzzi Jr., MD, of the MGH Cardiology Division, the paper's co-lead author and principal investigator of the 2005 PRIDE Study, from which the data for the current report was generated. "It also is notoriously difficult to identify those heart failure patients at the highest risk of death, so biomarker screening to assist with prognostication has been studied and increasingly implemented over the past several years."
Januzzi and his collaborators have published several studies showing that testing for a protein called NT-proBNP can aid the diagnosis of heart failure in patients coming to hospital emergency rooms with shortness of breath and can identify those at increased risk of dying within the coming year. Since many biological factors and processes lead to heart failure, the researchers recognized that testing for several complementary biomarkers would probably give the best and most complete information for individual patients.
In addition to NT-proBNP, which is an indicator of stress in the heart muscle, they also screened for levels of galectin-3, produced by cardiac inflammatory cells, and apelin, a protein thought to play a role in heart muscle contraction that was suggested to be useful for diagnosis and prognosis in heart failure patients. The investigators tested blood samples gathered in the PRIDE study – which measured NT-proBNP levels in almost 600 patients who came to the MGH Emergency Department with shortness of breath – for levels of the two proteins. Measurements of the potential new markers were correlated with the detailed PRIDE study follow-up information to search for associations between protein levels and patient outcomes.
Elevated NT-proBNP levels were the strongest indicator of heart failure in the study population, but galectin-3 levels also were markedly increased in a significant proportion of those with heart failure. In addition, galectin-3 was the most powerful marker of the short-term risk for death. Importantly, the researchers showed that the highest risk of short-term death or recurrence of heart failure symptoms was seen in patients with elevations in both NT-proBNP and galectin-3. Contrary to prior findings, however, apelin did not prove useful for either diagnosis or prognosis, a finding that, Januzzi notes, "may lead investigators away from this marker for future use in heart failure diagnosis and prognosis."
"The strong predictive power of galectin-3 underscores the fact that heart failure is also an inflammatory process," explains Roland van Kimmenade, MD, of University Hospital of Maastricht, the paper's co-lead author. "Cardiologists tend to forget that the heart is more than a hollow muscle and that only one third of the organ consists of muscle cells. Moreover, verifying the role of galectin-3 in heart failure may lead to new standards for therapeutic decision making or even the development of new agents that would inhibit this inflammatory cascade."
Januzzi agrees, "This is the first time a marker with putative inflammatory function has been shows to have potential diagnostic and especially prognostic value in heart failure, and the complementary nature of galectin with NT-proBNP for prognosis is an exciting finding." He adds, "We are going to be using the PRIDE study data to examine several other candidate markers that could lead to development of a comprehensive biomarker profile to guide targeted application of specific therapies." Januzzi is an assistant professor of Medicine at Harvard Medical School.
Additional co-authors of the report are Patrick Ellinor, MD, PhD, Adrian Low, MB, Abelardo Martinez, MD, and Calum MacRae, MB, ChB, PhD, of MGH Cardiology; and Umesh Shara, MD, PhD, Jaap Bakker, Harry Crijns, MD, PhD, Paul Menheere, PhD, and Yigal Pinto, MD, PhD, of University Hospital of Maastricht. The study was supported by grants from the Netherlands Heart Foundation and the William Marquard Fund for Cardiac Research. Several of the researchers receive support from Roche Diagnostics, which manufactures the NT-proBNP assay; and Pinto holds a patent on cardiovascular applications of galectin-3 testing.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare System, a Boston-based integrated health care delivery system.
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