Unraveling the pathophysiology of acute heart failure: An inflammatory proposal

Acute heart failure remains a major epidemic in the developed world, with more than 1 million hospitalizations annually in the United States alone.1 Despite the substantial clinical and economic burden of this syndrome, it remains poorly understood—indeed, no consensus exists as to whether acute heart failure is a distinct clinical entity or simply an exacerbation of chronic heart failure. This lack of fundamental insight stands in marked contrast to current understanding of other prevalent acute cardiovascular disorders such as acute coronary syndromes. The landmark discovery by DeWood of the fundamental role of acute thrombosis in myocardial infarction2 has led to therapeutic advances aimed at the underlying thrombus, such as thrombolytic therapy and glycoprotein 2b/3a receptor blockers3, 4 In acute heart failure, the lack of such fundamental insights has resulted in correspondingly limited development of new therapies, as evidenced by the similarities between recommendations for acute heart failure treatment published in 1974 (oxygen, morphine, nitrates, and loop diuretics)5 and current clinical practice. Limited data on the triggers for acute heart failure have proposed a heterogeneous mix of biologic and patient-related factors, including ischemia, arrhythmias, hypertension, and noncompliance.6, 7, 8 Although all these factors clearly can contribute to heart failure decompensation, more fundamental understanding of the biological basis for acute heart failure is lacking.

The cytokine hypothesis of heart failure suggests that heart failure progression occurs in response to the adverse cardiovascular effects of inflammatory cytokine cascades on myocardial function. Multiple lines of evidence from animal models and human studies support the concept that inflammatory cytokines may play an important role in heart failure pathophysiology.9 Despite this substantial body of evidence, however, large randomized trials of anticytokine therapy focused on blocking the effects of tumor necrosis factor α (TNF) have failed to demonstrate any benefit in chronic heart failure.10, 11 A variety of hypotheses have been proposed to explain this surprising lack of efficacy, including TNF as the wrong target, limitations of pharmacological TNF blockade, or the rejection of the cytokine hypothesis altogether.12

In this issue of the Journal, Mueller et al provide potentially important data on a link between inflammation and acute heart failure. In a cohort study of 217 patients presenting with acute dyspnea determined to be due to heart failure, they demonstrate that elevation of C-reactive protein (CRP) at the time of acute heart failure presentation is associated adverse short- and long-term clinical outcomes. Patients with admission CRP values in the highest tertile had higher rates of ICU admission and inhospital mortality, but also had significantly higher rates of rehospitalization and long-term mortality. These results persisted despite adjustment for an array of other clinical variables on admission. These data raise a key issue in understanding the role of inflammatory mediators in heart failure progression: Is inflammation (as represented by CRP elevation) the cause or the result of acute heart failure decompensation? As the authors speculate, CRP elevation may be the result of bacterial or endotoxin translocation from the bowel during mesenteric ischemia in the setting of acute heart failure, a concept that has been proposed by other investigators.13, 14 Such a hypothesis would suggest that CRP elevation is primarily a result, rather than a fundamental cause, of hemodynamic deterioration. Alternatively, elevated CRP may reflect a greater burden of proinflammatory cytokines that acts as a trigger for decompensation and also plays a role in the long-term progression of heart failure. Such a hypothesis is supported by animal data demonstrating that acute increases in inflammatory mediators can recapitulate the phenotype of acute heart failure with increased diastolic stiffness, ventricular dysfunction, capillary permeability, and pulmonary edema.15, 16 In light of the data showing increased diastolic dysfunction after infusion of TNF or interleukin (IL)-6, it is notable that in the current study, CRP was most elevated in patients with decompensated heart failure and preserved systolic function, and retained its strong association with adverse outcomes regardless of ejection fraction.

One hypothesis raised by these data is that “inflammatory acute heart failure” may represent a distinct subtype of acute heart failure that may be unrelated to the existence of chronic heart failure. This hypothesis is supported by the findings of Milo et al17 of persistently high IL-6 and CRP levels at 2 months follow-up in patients with acute heart failure without ischemic, arrhythmic, or valvular etiology. If indeed inflammatory antihemophilic factor A represents a distinct clinical syndrome triggered by imbalance between pro- and antiinflammatory cytokines, could antiinflammatory therapy (either anticytokine therapy or less specific forms of immunomodulation) be a form of acute rather than chronic heart failure therapy? This testable hypothesis could explain the failure of previous anti-TNF studies, which focused on chronic treatment in patients with chronic heart failure due to severe systolic dysfunction.

Some limitations of the study by Mueller et al deserve mention. As the authors note, CRP is an acute phase reactant and a nonspecific marker of systemic inflammation. Further research will be needed to define which specific inflammatory mediators are most important in the pathogenesis of acute heart failure. Some patients in their study appeared to have concomitant infections, although the association of CRP with outcomes CRP persisted even when these patients were excluded. Finally, the authors do not have serial measurements of CRP, which would provide insight into the role of persistent inflammatory activation in long-term heart failure progression.

In addition to the association of CRP with outcomes, it is notable that B-type natriuretic peptide (BNP) and troponin were also most elevated in patients with the highest tertile of CRP values. This finding underscores the fact that these 3 markers represent potentially important and interrelated processes in the pathophysiology of acute heart failure—myocyte necrosis (troponin), hemodynamic overload (BNP), and inflammation (CRP). Notably, these same 3 markers have also emerged as central to the understanding of risk stratification and therapeutic selection in patients with acute ischemic heart disease.18 Development of multimarker strategies that incorporate these markers (and others) will potentially facilitate clinical care and aid in the development of new therapies. Importantly, different markers may be most useful at different time points and in differing clinical situations. Despite the well-described relationship between BNP and heart failure, admission BNP is a relatively weak predictor of long-term outcomes and does not appear to be as prognostically useful as BNP levels after acute therapy (at the time of discharge).19 The prognostic power of BNP levels at discharge may reflect adequacy (or lack thereof) of acute treatment or the degree of underlying chronic heart failure. Significant ongoing research will be needed to optimize use of available markers for selecting and monitoring response to treatment. Theoretically, measurement of CRP and troponin (which reflect inflammatory or ischemic triggers) may be more useful at the time of hospitalization, whereas BNP levels during and at the completion of hospitalization may reflect adequacy of treatment and allow appropriate intensity of follow-up. Future studies focused on careful description of acute heart failure “phenotype,” measurement of multiple markers, and use of serial measurements during and after hospitalization will be required to improve fundamental understanding and lead to new treatment strategies for this highly morbid cardiovascular disorder.