Author + information
- †Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts
- ‡Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri
- ↵∗Reprint requests and Correspondence:
Dr. James Januzzi, Jr., Cardiology Division, Massachusetts General Hospital, 32 Fruit Street, Yawkey 5984, Boston, Massachusetts 02114.
Since the first description by Elster et al. (1) in 1956 of the presence of elevated concentrations of C-reactive protein (CRP) in patients with heart failure (HF), the importance of inflammation in the genesis and progression of the diagnosis has gained substantial attention. Indeed, since this first seminal observation, many thousands of research publications focused on broad-based aspects of inflammation in HF have been published. Studies in this area have focused not only on mechanistic aspects of inflammation and how it affects the heart, but several important trials have also attempted to modulate inflammation in patients with HF with the hopes that such anti-inflammatory therapies might retard ventricular remodeling and improve outcomes; such trials met with little success (2,3) despite early phase data suggesting the treatments studied might actually be beneficial.
The potential causes of inflammation in patients with HF are numerous, including the activation of innate immune responses following tissue injury, neurohormonal activation, oxidative stress, as well as translocation of bacteria or their products from the gut due to intestinal edema (4). Regardless of trigger, mechanistically, inflammation has been linked to numerous deleterious processes in HF, including progression of myocardial remodeling, cardiomyocyte necrosis and/or apoptosis, endothelial dysfunction, as well as onset of relevant comorbidities in HF, such as worsening cachexia, insulin resistance, anemia, and sarcopenia. Accordingly, a better grasp of how to assess the presence of inflammation and/or its mediators remains a clinically relevant challenge if one is planning therapeutic interventions that are designed to delimit the ongoing tissue injury secondary to sustained inflammatory responses in HF. It is in this context that measurement of circulating biomarkers reflective of inflammation has gained interest.
Besides CRP, several novel inflammatory biomarkers in HF have been identified and examined in great detail (5,6). With very few exceptions, the vast majority reflect or participate in innate and/or cell-mediated immune processes; these include cytokines (interleukins, tumor necrosis factor [TNF]), adipokines (adiponectin), cytokine receptors (such as soluble ST2 and soluble TNF receptors), markers of macrophage activation (e.g., galectin-3, pentraxin-3), and even lymphocyte count, to name a few. However, and somewhat surprisingly, there are relatively few biomarkers that reflect activation of humoral immunity in patients with HF syndromes.
Abnormal humoral immunity—typically assessed through measurement of immunoglobulins or complement proteins—is pivotally important in the genesis of several non-cardiovascular diseases and may be prognostic in other diagnoses; however, the role of abnormalities in humoral immunity and HF is less clear. Abnormal humoral immune function has been reported in small case series of patients with HF (usually in association with autoantibodies against troponin or β1-receptors), or following myocarditis. Several clinical studies using immunoadsorption against specific autoantibodies (e.g., the β1-receptor) have shown beneficial effects in small clinical trials in patients with dilated cardiomyopathy and advances in aptamer technology have allowed for the development of mutated cyclopeptides that bind to and neutralize circulating anti-β1-receptor antibodies. Preliminary data from studies of such peptides suggest they are safe and well-tolerated, and may promote reversal of cardiac dysfunction by blocking myocardial damage (7).
These small advances notwithstanding, the role of humoral immunity in patients with HF remains poorly understood. Shedding some light on the subjects, Shantsila et al. (8) recently suggested elevation in combined free light chains (cFLCs) (a sum of kappa and lambda FLCs) were independently prognostic for death or readmission in patients with acutely decompensated HF. However, this study was small, leaving opportunity for a more robust study of this observation.
In this issue of JACC: Heart Failure, Jackson et al. (9) report a larger and more robustly analyzed assessment of the prognostic importance of cFLCs among patients following recent hospital discharge for acutely decompensated HF. In this analysis of 628 subjects, predominantly male, with mainly HF with reduced ejection fraction and mean age of nearly 71 years, a graded risk for death across cFLC quartiles was noted; a cFLC concentration in the highest quartile was independently predictive of a higher rate of death across a mean of 3 years of follow-up, with a hazard ratio of 1.49 (p = 0.01), even when vigorously adjusted for numerous relevant clinical and biochemical markers of risk, the latter including B-type natriuretic peptide (BNP), CRP, red cell distribution width, and renal function.
It is a challenge to understand why cFLCs were as prognostic as they were in this report. Concentrations of cFLC were higher with age, in male subjects, and in those with more comorbidities, but curiously cFLC values were not associated with ejection fraction or worse HF symptoms. Disappointingly, no strong association between HF therapies and cFLCs were found. Substantial co-linearity existed between cFLCs and multiple prognostic biomarkers in this analysis, with higher concentrations of BNP, blood urea nitrogen, creatinine, CRP, uric acid, and glycohemoglobin seen in those with higher cFLC. Despite this fact, in carefully performed statistical analyses, high concentrations of cFLCs were robust predictors of death in Cox proportional hazards modeling, remaining significant in C-statistic assessment, and predicting shorter time to first event either alone or in conjunction with BNP; cFLCs also reclassified risk (mainly downwards, predicting better outcomes in those with low cFLC values). The authors are to be congratulated in the rigor of their analyses, which included not only discrimination, calibration, and reclassification efforts, but also adjusting their models in a robust manner, leaving less doubt about the validity of their result.
Limitations of the analysis include the lack of re-hospitalization data or a validation set. Further, while robust, the statistical model did not adjust for other important biomarkers of inflammation, such as sST2, which reflects both inflammation and myocardial remodeling; indeed, one of the important questions raised by the study by Jackson et al. (9) is whether the measurement of cFLCs is additive to inflammatory biomarkers besides CRP in the setting of HF. The absence of serial cFLC measurement in these subjects is a limitation as well; in the previous analysis by Shantsila et al. (8), cFLC concentrations did not change over a 3-month period, so it is hard to know if serial measurement would add substantially to a baseline value. Finally, while Jackson et al. (9) adjusted their model for both creatinine as well as cystatin c, it is hard to discount the potential that cFLC concentrations simply reflect a more sensitive measure of glomerular filtration, itself so very powerfully prognostic in this population.
The main question now is what to make of these results and how to proceed. Careful assessment of novel prognostic biomarkers in HF is critical (5,10); indeed, we have previously articulated expectations for any novel biomarker (Table 1). The reader should understand it is reasonably easy to identify new assays that may have prognostic meaning in HF—a disease state associated with considerable disarray of a multitude of organ systems—but the great majority of such prognostic biomarkers leave us wanting, as their results do not contribute to mechanistic understanding of HF pathophysiology or add unique information regarding therapeutic opportunities for patients with abnormal results. Simply put, if a biomarker cannot extend the mechanistic or therapeutic understanding in this disease, it is hard to be enthusiastic about prognostic results that have ambiguous explanation.
One hopes the observation of prognostic importance from cFLC measurement might lead to either a better understanding of HF pathophysiology (particularly the role of adaptive immune responses in affected patients), or inform more precise treatment as a companion diagnostic. In this vein, could recognition of elevated cFLCs present opportunity to modulate humoral immunity with agents suppressing B cell function and/or identify the need for immunoadsorption? Indeed, such “precision” care is the ultimate goal for clinical/translational study of biomarkers in any disease state, allowing for a more “black and white” view of patients. For now, however, the measurement of cFLCs in HF remains an interesting observation providing only multiple shades of grey. Further study will be of help in this area.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Januzzi has received grant support from Siemens, Thermo Fisher, Singulex, Amgen, and Prevencio; consulting fees from Roche Diagnostics, Critical Diagnostics, Sphingotec, and Novartis; and serves on the Data Safety and Monitoring Board for an Amgen trial. Dr. Mann has reported that he has no relationships relevant to the content of this paper to disclose.
- American College of Cardiology Foundation
- Mann D.L.,
- McMurray J.J.,
- Packer M.,
- et al.
- Chung E.S.,
- Packer M.,
- Lo K.H.,
- Fasanmade A.A.,
- Willerson J.T.,
- for the Anti-TNF Therapy Against Congestive Heart Failure Investigators
- van Kimmenade R.R.,
- Januzzi J.L. Jr..
- Jackson C.E.,
- Haig C.,
- Welsh P.,
- et al.
- Ahmad T.,
- Fiuzat M.,
- Pencina M.J.,
- et al.