Ing. Biomedica

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Medical Progress

Biomarkers in Heart Failure
Eugene Braunwald, M.D.

From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and the Department of Medicine, Harvard Medical School — both in Boston. Address reprint requests to Dr. Braunwald at theTIMI Study Group, 350 Longwood Ave., Boston, MA 02115, or at ebraunwald@partners.org. N Engl J Med 2008;358:2148-59.
Copyright © 2008 Massachusetts Medical Society.

H

eart failure, a major and growing public health problem, appears to result not only from cardiac overload or injury but also from a complex interplay among genetic, neurohormonal, inflammatory, and biochemical changes actingon cardiac myocytes, the cardiac interstitium, or both. An increasing number of enzymes, hormones, biologic substances, and other markers of cardiac stress and malfunction, as well as myocyte injury — collectively referred to as biomarkers — appear to have growing clinical importance. Although biomarkers include genetic variants, clinical images, physiological tests, and tissuespecimen biopsies,this review focuses on biomarkers derived from the blood or urine other than serum levels of hemoglobin, electrolytes, liver enzymes, and creatinine, which are routinely determined as part of clinical care. Morrow and de Lemos1 have set out three criteria a biomarker should fulfill to be useful clinically. First, accurate, repeated measurements must be available to the clinician at a reasonablecost and with short turnaround times; second, the biomarker must provide information that is not already available from a careful clinical assessment; and finally, knowing the measured level should aid in medical decision making. Although relatively few of the biomarkers discussed in this review satisfy all three criteria, many appear to provide important information regarding the pathogenesis ofheart failure or the identification of subjects at risk for heart failure or appear to be useful in risk stratification, in the diagnosis of heart failure, or in monitoring therapy. Many biomarkers may be risk factors themselves and therefore may be potential targets of therapy. Although no specific classes for biomarkers are accepted, I propose that they could be divided into six categories, as wellas a seventh category of new biomarkers that have not yet been fully characterized (Table 1).

INFL A M M AT ION
Inflammation is important in the pathogenesis and progression of many forms of heart failure, and biomarkers of inflammation have become the subject of intense inquiry (Table 2).3 Interest in the presence of inflammatory mediators in patients with heart failure began in 1954, when acrude assay for C-reactive protein, a protein that appears in the serum in a variety of inflammatory conditions, became available. A study published in 1956 reported that C-reactive protein was detectable in 30 of 40 patients with chronic heart failure and that heart failure was more severe in those with higher levels of C-reactive protein.4 Subsequently, C-reactive protein was described as anacute-phase reactant synthesized by hepatocytes in response to the proinflammatory cytokine interleukin-6.5 The use of C-reactive protein as a biomarker became more common when a low-cost, high-sensitivity test for C-reactive protein was developed.6 Multivariate analysis indicated that increased C-reactive protein level is an independent predictor of adverse outcomes in patients with acute or
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Medical Progress

Table 1. Biomarkers in Heart Failure. Inflammation*†‡ C-reactive protein Tumor necrosis factor α Fas (APO-1) Interleukins 1, 6, and 18 Oxidative stress*†§ Oxidized low-density lipoproteins Myeloperoxidase...