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N-terminal-pro-B-type natriuretic peptide in cardiogenic shock: a marker ready for prime time or a therapeutic target?

Although the incidence of cardiogenic shock (CS) remained stable at 7% to 9% in all acute myocardial infarction (AMI) admissions into the early part of this decade (1), reports suggest a decrease in the most recent period—a decrease attributed to a marked increase in the utilization of interventional therapy as well as improvements in medical therapy (2, 3). When shock secondary to ventricular pump failure does occur, early revascularization improves long-term survival and is therefore now the recommended therapy when it can be performed within 18 hours of shock onset (4). Nonetheless, mortality remains high, with even the most positive registries reporting inhospital rates in the 40% range for patients selected for percutaneous coronary intervention. Although percutaneous coronary intervention techniques and associated antiplatelet and anticoagulant pharmacotherapy have improved and continue to improve since the publication of the should we emergently revascularize occluded coronary arteries in cardiogenic shock trial, these advances have not led and are unlikely to lead to dramatic improvements in outcome. Although mechanical assist, in particular with the intra-aortic balloon pump, now constitutes an American Heart Association/American College of Cardiology indication in the setting of CS, this consensus indication is based on data from registries with all of their caveats and limitations, and one positive subgroup analysis of a small negative trial (5). Furthermore, any possible additional benefits of left ventricular assist devices are as yet unproven (6, 7). Factors other than pure ventricular pump failure have been suggested as having, if not an entirely causative, at least a possible contributory role in the pathophysiology of CS. Observations that interleukin-6 and tumor necrosis factor-alpha are increased in patients with AMI who go on to develop CS (8), or that patients in CS on average have normal rather than elevated systemic vascular resistance, despite vasopressor therapy (9), point to a contributory effect of systemic inflammation. Interleukin-6 is found to be elevated in patients with CS (10), especially in those who subsequently develop multisystem failure, raising the possibility that the cytokine could be a useful marker of particularly high risk in CS (11). More recently, B-type natriuretic peptide (BNP), a natriuretic and diuretic hormone produced as the prohormone proBNP in ventricular as well as atrial myocytes with subsequent cleavage to the active BNP and inactive terminal fragment N-terminal-pro BNP (Nt-proBNP), likely in response to wall stretch (12), has also been suggested as a useful marker of high risk in AMI. In the Enoxaparin Tenectaplase-Tissue-Type Plasminogen Activator With or Without Glycoprotein IIb/ IIIa Inhibitor as Reperfusion Strategy in ST-Segment Elevation Myocardial Infarction-Thrombolysis in Myocardial Infarction-23, higher baseline levels of BNP in patients presenting with ST-elevation myocardial infarction were associated with impairment of reperfusion after fibrinolytic therapy, whereas patients in the highest BNP concentration quartile had an 11-fold risk of dying by 30 days compared with those in quartiles one through three (13). Similarly, Nt-proBNP has previously been shown to be predictive of myocardial damage, development of CS, and in-hospital as well as 1-year mortality (14, 15). In this issue of Critical Care Medicine, Jarai et al (16) report the results of a two-center retrospective study investigating the association between the level of Nt-proBNP alone as well as in combination with interleukin-6, and outcome in 48 patients in CS secondary to AMI, and 9 others with shock due to various other etiologies. Their findings, that high above the median plasma level of Nt-proBNP is associated with worse outcome, extend our knowledge regarding the utility of this marker as an outcome predictor in patients suffering an AMI event to the most severely ill subset—those with complicating CS. Indeed, it would be of considerable utility to the clinician to be able to, even in the apparently extremely highrisk setting of CS, to further identify those who are more likely to have a relatively benign course, as well as, and more importantly, those who will do poorly with current therapies. The reported additional information that a combination of high levels of Nt-proBNP and interleukin-6 further crystallizes a subset at extremely high risk is also noteworthy. Fewer than 10% of patients with both values above but more than 70% of those with both values below the high-risk cutpoint survived for 30 days. Further analyses revealed that in the presence of a high Nt-proBNP level, patients had a high mortality irrespective of the presence or absence of renal dysfunction, a characteristic that in all prior reports has been shown to identify a population at high risk for shortas well as long-term mortality. Finally, patients with Nt-proBNP levels above the median had a very high 30-day mortality irrespective of whether or not they had had a successful percutaneous coronary intervention. Although these observations are important, by the authors’ own admission, they are based on a retrospective analysis and, by any definition, a small number of observations. The latter limitation is especially important when the 49-patient AMI cohort is further subdivided to explore associations among baseline characteristics or revascularization status, NtproBNP levels, and outcome. Although there can be enthusiasm about a biomarker or a combination of biomarkers that *See also p. 1837.