American Heart Journal
Volume 152, Issue 1 , Pages 1-3, July 2006

Biomarker screening for cardiac dysfunction: The more the merrier?

  • W.H. Wilson Tang, MD

      Affiliations

    • Corresponding Author InformationReprint requests: W.H. Wilson Tang, MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, F25, Cleveland, OH 44195.

Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland OH

Received 31 October 2005; accepted 19 January 2005.

Article Outline

 

The traditional view of screening for heart failure has relied upon the visual confirmation of impaired left ventricular function or abnormal dilatation or hypertrophy of the cardiac chambers (so-called stage B heart failure1). It is built on the assumption that the development of overt heart failure depends on a primary “lesion” in the heart that can be visualized by imaging modalities even in the asymptomatic “latent” phase as unsuspected left ventricular systolic dysfunction (LVSD). Detection of the counter-regulatory hormonal response to this lesion (in particular B-type natriuretic peptide or BNP) has also been utilized as a way to quantify dysfunction. Indeed, several population studies of heart failure screening have indicated the potential utility of limited ultrasonography2, 3, 4, 5 and/or natriuretic peptides6, 7, 8, 9, 10 to detect early cardiac dysfunction. However, the results have been mixed, largely due to the potential cost burden of imaging modalities and the nonspecific nature of biomarker testing.11

In this issue of the Journal, Ng et al12 seek to improve the efficiency of detecting LVSD by combining the use of a biomarker of myocardial stress (N-terminal pro-BNP or N-BNP) with two inflammatory biomarkers that have been heretofore associated with underlying atherosclerotic burden and progression. This is not surprising, considering the fact that most patients with heart failure may have myocardial ischemia as their primary cause. Myeloperoxidase (MPO) and C-reactive protein (CRP) are two cardiac biomarkers, offered in standard clinical laboratories, that have been implicated in the disease progression of inflammation and myocardial ischemia. Their increasing popularity stems from a wealth of scientific evidence supporting their potential role in the pathogenesis of coronary atherosclerosis. In the detailed analysis of Ng et al,12 combining the three biomarkers yielded a favorable and cost-effective screening strategy that may detect one case of LVSD for as few as 7 echocardiograms performed. Their results are superior to that of using N-BNP alone, and their accuracies are highly comparable with many well-established cancer screening tests (such as prostate-specific antigen screening for prostate cancer or mammogram screening for breast cancer). Although some investigators may have previously suggested an improvement in diagnostic yield and cost-effectiveness of biomarker testing by focusing on high-risk subgroups,13 Ng et al12 have convincingly demonstrated that at least 60% of LVSD will be missed if a focused high-risk screening strategy is implemented in their population.

Perhaps the most intriguing and unexpected finding in this paper is that the diagnostic accuracy of plasma MPO, traditionally a marker of inflammation, is equivalent to that of plasma N-BNP for detection of LVSD. Despite the limitations of the relatively small “event rate,” the specificity of plasma MPO was higher than that of plasma N-BNP (74.1% vs 40.5%, respectively). This comes as a surprise, particularly when as many as 60% of patients with LVSD in their study had no history of ischemic heart disease.12 These findings may imply that MPO (and to a lesser extent CRP) may have an important pathogenic role in cardiac remodeling, independent of atherosclerotic progression. Inflammation is not a new concept in heart failure.14 Indeed, MPO is a leukocyte-derived enzyme that catalyzes the formation of nitric oxide–derived oxidants, which in turn can cause myocardial damage by catalyzing the initiation of lipid peroxidation. In animal studies, preservation of left ventricular function has been observed in both a coronary artery ligation model and in an ischemia-reperfusion model in MPO null mice.15, 16 In humans, both MPO and CRP have been associated with the development of congestive heart failure in large epidemiological studies.17, 18 These findings suggest that MPO may provide a mechanistic link between inflammation and impaired cardiac remodeling. Plasma MPO levels have found to be elevated in chronic systolic heart failure,19 whereas elevated plasma CRP levels have been associated with poor prognosis in the setting of stable heart failure—both independent of underlying heart failure etiology.20, 21 These observations, combined with those from Ng et al,12 may support the hypothesis that inflammation may play an important pathogenic role in cardiac remodeling in early phases of heart failure even before the onset of symptoms. Indeed, the impact of specific genetic, metabolic, inflammatory, neurohormonal, and environmental factors on disease progression in this early phase of heart failure is unclear and perhaps largely unknown, partly because large populations of asymptomatic LVSD patients are difficult to identify and follow.

Another point of contention is that heart failure screening studies to date have relied on the correct identification of cardiac dysfunction as their primary objective. Therefore, subjects with elevated biomarkers who have yet to develop cardiac dysfunction are considered to be false negatives. What is still unclear is whether this false-negative population will subsequently develop cardiac dysfunction, that is, whether elevated biomarkers identify an ongoing process that is undetectable by cardiac imaging. This concept is supported in part by the observation that higher levels of plasma BNP in the general population confer poorer long-term prognosis.7, 22 It is certainly conceivable (though unproven) that sequential measurements using a multimarker approach may identify a higher-risk population that warrants more careful follow-up and more aggressive medical intervention to prevent the development of heart failure. At this point, however, there is yet to be an indication for a change in medical regimen based on an elevated plasma N-BNP, CRP, and/or MPO level.

Although there are still many challenges ahead, the benefit of this multimarker approach is that all three biomarkers have commercially available assays for clinical implementation. However, it should be emphasized that assay characteristics vary widely, particularly with regards to their diagnostic properties and coefficients of variation.23 Therefore, the cutoff values from the research assays described by Ng et al12 cannot be directly translated to currently available laboratory assays. Much work is needed for different assays to harmonize the testing results specifically for population screening purposes. Furthermore, the dynamics of biomarker elevation may vary widely with different forms of cardiomyopathy. Using the same multimarker panel, patients with familial or drug-induced cardiomyopathy (with direct cytoskeletal alterations) may present with a different permutation of cutoff values than those with infective or ischemic cardiomyopathy (where inflammation may play a prominent role). The exact permutation of biomarkers used (and their cutoff values with respect to different patient populations) will likely generate a lot of discussion and debate—something that is relatively less controversial for echocardiography. Regardless, the biggest challenge in heart failure screening will likely be the generation of sufficient political will, resources, and strategies to adopt and implement an acceptable screening practice. Containing the costs of running these assays by providing them as a panel is desirable, but effective screening programs that yield long-term clinical benefits (rather than their cost-effectiveness) will be the key to their adoption. With the data presented by Ng et al,12 a multimarker screening idea is promising and will hopefully move us closer to a testable screening strategy and a goal to better preserve myocardial function.

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References 

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 Dr Tang previously received a one-time honorarium from Abbott Diagnostics Inc and from Roche Diagnostics Inc.

PII: S0002-8703(06)00049-4

doi:10.1016/j.ahj.2006.01.002

American Heart Journal
Volume 152, Issue 1 , Pages 1-3, July 2006

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