Author + information
- Received January 16, 2013
- Revision received February 28, 2013
- Accepted March 6, 2013
- Published online June 1, 2013.
- Nishant R. Shah, MD∗,
- Mark C. Bieniarz, MD†,
- Sukhdeep S. Basra, MD, MPH‡,
- Robert D. Paisley, MD§,
- Pranav Loyalka, MD‖,
- Igor D. Gregoric, MD‖,
- Douglas L. Mann, MD¶ and
- Biswajit Kar, MD‖∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Biswajit Kar, Center for Advanced Heart Failure, University of Texas Health Sciences Center, 6410 Fannin Street, Suite 920, Houston, Texas 77030.
Objectives The aim of this study was to characterize levels of serum biomarkers in patients with severe refractory cardiogenic shock (SRCS) and to document temporal changes in these levels during restoration of circulation.
Background Patients with SRCS have been challenging to study because of their rapidly changing clinical condition while undergoing multiple simultaneous interventions.
Methods Twenty-one patients with SRCS received circulatory support via a percutaneously implanted ventricular assist device (PVAD). Serum samples obtained prior to PVAD support initiation, at 24 h of PVAD support, and at 7 days of PVAD support were assayed for B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein (hsCRP), soluble tumor necrosis factor receptor-1 (sTNFR1), soluble Fas (sFas), soluble Fas ligand (sFasL), endothelin-1, and procollagen III N-terminal peptide (PIIINP). Baseline biomarker levels were qualitatively compared to reference values; levels at 24 h of PVAD support and at 7 days of PVAD support were compared to baseline using 2-tailed Wilcoxon matched pair signed rank tests with Bonferroni correction for multiple comparisons.
Results These patients with SRCS had elevated serum levels of BNP, hsCRP, sTNFR1, endothelin-1, and PIIINP. Ventricular unloading and restoration of circulation via PVAD support in patients with SRCS were associated with reductions in serum BNP, sFas, and endothelin-1 levels and increases in serum sFasL and PIIINP levels.
Conclusions This study characterizes several important baseline serum biomarker levels in patients with SRCS and introduces a novel PVAD-based protocol with the potential to "reverse"-model the pathophysiology of cardiogenic shock.
Cardiogenic shock is a state of end-organ hypoperfusion resulting from severe left ventricular and/or right ventricular dysfunction. Accordingly, treatment options in the management of acute cardiogenic shock are directed at augmenting cardiac output and restoring circulation and have historically included revascularization (1–3), intravenous inotropic/vasopressor agents, and intra-aortic balloon pump counterpulsation (4–7). More recently, percutaneously implanted ventricular assist devices (PVADs), which can be emergently inserted in the cardiac catheterization laboratory, have been shown to quickly reverse and stabilize the terminal hemodynamic compromise of severe refractory cardiogenic shock (SRCS) (8–10).
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Aside from clinical benefits, the relatively stable and controlled manner in which PVAD support effects ventricular unloading and restoration of circulation has created a novel research environment. For the first time in human subjects, it is possible to directly study the temporal relationships between hemodynamic changes and the biochemical pathways previously implicated in cardiogenic shock, including tissue ischemia, systemic inflammation, cellular apoptosis, activation of the neurohormonal axis, and extracellular matrix turnover (11). More simply, PVAD support potentially allows for "reverse"-modeling of the pathophysiology of cardiogenic shock. On that basis, the primary objectives of this single-center, prospective, observational study were to: 1) characterize levels of serum biomarkers of ventricular wall stress, inflammation, apoptosis, neurohormonal axis activation, and extracellular matrix turnover during SRCS; and 2) document temporal changes in these levels during rapid ventricular unloading and restoration of circulation.
The study protocol was approved by the institutional review board at St. Luke’s Episcopal Hospital, Houston, Texas.
Twenty-one patients with SRCS received mechanical circulatory support via a PVAD capable of up to 4.5 l/min of assisted cardiac output. SRCS was characterized by a systolic blood pressure of ≤90 mm Hg, a cardiac index of ≤2.0 l/(min·m2), and evidence of end-organ failure despite inotrope/vasopressor support (any combination of dopamine, norepinephrine, vasopressin, epinephrine, and/or phenylephrine) with or without intra-aortic balloon pump counterpulsation. The clinical decision to initiate PVAD support was made prior to study enrollment.
The method of PVAD insertion has been described elsewhere (8). Briefly, a 21-F left atrial cannula, inserted by means of a venous trans-septal puncture via the femoral vein, channels blood into the pump, and a 15- to 17-F femoral artery cannula carries the blood to the systemic arterial circulation. After insertion, heparin is administered continuously to achieve a targeted activated partial thromboplastin time of 60 to 80 s. The PVAD flow rate is constantly adjusted to maintain mixed venous oxygen saturation >70% and mean arterial pressure >60 mm Hg, and to facilitate aortic valve opening. Patients showing adequate hemodynamics and improving end-organ function at a PVAD flow rate of 2 l/day for 2 days were gradually weaned off of PVAD support. Those who did not meet these criteria were transitioned to definitive therapy (i.e., revascularization, valve repair/replacement) or a surgically implanted VAD or were referred for orthotopic heart transplantation.
Study enrollment was initiated by obtaining informed consent from each patient’s surrogate decision maker using a consent form approved by the institutional review board at the Texas Heart Institute/St. Luke’s Episcopal Hospital, Houston, Texas. After consent was obtained, 60-ml whole blood samples were obtained from each patient at three different time points: 1) immediately prior to PVAD support initiation (baseline); 2) at 24 h of PVAD support; and 3) at 7 days of PVAD support. Whole-blood samples were immediately transferred to citrate-treated, EDTA-treated, or nontreated blood-collection tubes and centrifuged at 4,500 rpm for 15 min at 4°C. Serum supernatants from each tube were aliquotted and stored at –80°C.
Serum B-type natriuretic peptide (BNP) was selected as a surrogate marker of ventricular wall stress. Serum high-sensitivity C-reactive protein (hsCRP) and serum soluble tumor necrosis factor receptor-1 (sTNFR1) were selected as surrogate markers of inflammation. Serum soluble Fas (sFas) and serum soluble Fas ligand (sFasL) were selected as surrogate markers of apoptosis. Serum endothelin-1 was selected as a surrogate marker of neurohormonal axis activation. Finally, serum procollagen III N-terminal peptide (PIIINP) was selected as a surrogate marker of extracellular matrix turnover. Aliquotted samples were assayed in the following manner: 1) hsCRP and BNP were quantified by the laboratory at St. Luke’s Episcopal Hospital; 2) sFas, sFasL, and sTNFR1 were quantified using commercially available colorimetric immunoassay kits (R&D Systems, Minneapolis, Minnesota, and Enzo Life Sciences International, Inc., Plymouth Meeting, Pennsylvania); 3) endothelin-1 was quantified using commercially available chemiluminescent immunoassay kits (R&D Systems); and 4) PIIINP was quantified using commercially available radioimmunoassay kits (Orion Diagnostica, Espoo, Finland).
Clinical data were abstracted prospectively after study enrollment. Baseline clinical characteristics abstracted at initiation of PVAD support included age, sex, body mass index, cardiac history, medical comorbidities, etiology of cardiogenic shock, circulatory and respiratory support, and hemodynamic parameters. Clinical data collected after PVAD support initiation included hemodynamic parameters, inotrope/vasopressor support, number of packed red blood cell transfusions, and surveillance blood culture results.
Statistical software SPSS version 18 (SPSS Inc., Chicago, Illinois) was used for data analysis. Mean ± SD or counts and proportions were calculated for all patient baseline characteristics. Serum biomarker data were tested for normality and each was found to be skewed. Accordingly, medians and interquartile ranges are reported for each biomarker at each time point. All biomarker data at 24 h of PVAD support and at 7 days of PVAD support were compared to baseline data using 2-tailed Wilcoxon matched-pair signed rank tests. Given multiple measurements for each biomarker, Bonferroni correction was applied, and p values of <0.017 were considered statistically significant.
Baseline-characteristic data at PVAD support initiation are included in Table 1. Baseline hemodynamic parameters and inotrope/vasopressor support are included for comparison with the same values at 24 h and 7 days of PVAD support in Table 2. One patient was undergoing active CPR at PVAD support initiation. The mean duration of PVAD support was 9.3 ± 4.8 days. Between initiation and 24 h of PVAD support, 10/21 patients (48%) received at least one packed red blood cell transfusion. Only 1 patient had a positive surveillance blood culture between initiation and 24 h of PVAD support. A total of 14 of 21 patients (67%) remained on PVAD support for ≥7 days. Of these patients, 10/14 (71%) received at least one packed red blood cell transfusion between 24 h and 7 days of PVAD support, and none of the patients had a positive surveillance blood culture between 24 h and 7 days of PVAD support.
Baseline serum biomarker levels in patients with SRCS compared with lab- and kit-defined normal values
At baseline, patients with SRCS had elevated serum BNP (median: 823 pg/ml; lab-defined normal range: 0 to 100 pg/ml), hsCRP (median: 6.4 mg/dl; lab-defined normal range: 0 to 1.0 mg/dl), sTNFR1 (median: 3,690 pg/ml; kit-defined normal range: 749 to 1,966 pg/ml), endothelin-1 (median: 4.3 pg/ml; kit-defined normal range: 0.3 to 0.9 pg/ml), and PIIINP (median: 6.6 μg/l; kit-defined normal range: 2.3 to 6.4 μg/l). In contrast, patients with SRCS had normal baseline levels of serum sFas (median: 7,749 pg/ml; kit-defined normal range: 4,792 to 17,150 pg/ml) and serum sFasL (median: 43.6 pg/ml; kit-defined normal range: 39.8 to 145 pg/ml).
Serum biomarker levels at 24 h and 7 days of PVAD support versus baseline
Ventricular wall stress (BNP)
Compared with baseline, there was a statistically significant reduction in serum BNP at 24 h of PVAD support (p = 0.0024) and a strong trend toward continued reduction at 7 days of PVAD support (p = 0.0277).
Inflammation (hsCRP and sTNFR1)
Compared with baseline, there was a statistically significant increase in serum hsCRP at 24 h of PVAD support (p = 0.0019), but no significant difference at 7 days of PVAD support (p = 0.1961). Compared with baseline, there was no significant difference in serum sTNFR1 at 24 h of PVAD support (p = 0.6143) or at 7 days of PVAD support (p = 0.0995).
Apoptosis (sFas and sFasL)
Compared with baseline, there were statistically significant increases in serum sFas at 24 h of PVAD support (p = 0.0129) and at 7 days of PVAD support (p = 0.0046). Compared with baseline, there were statistically significant decreases in serum sFasL at 24 h of PVAD support (p = 0.0015) and at 7 days of PVAD support (p = 0.0159).
Neurohormonal axis activation (endothelin-1)
Compared with baseline, there were statistically significant decreases in serum endothelin-1 at 24 h of PVAD support (p = 0.0033) and at 7 days of PVAD support (p = 0.0037).
Extracellular matrix turnover (PIIINP)
Compared with baseline, there was a strong trend toward an increase in serum PIIINP at 24 h of PVAD support (p = 0.0325), but no significant difference at 7 days of PVAD support (p = 0.8444).
As opposed to patients with chronic heart failure, patients with SRCS have historically been challenging to study because of their rapidly changing clinical condition while undergoing multiple simultaneous interventions. For this reason, direct characterization of the active pathophysiology in these patients is distinctly lacking. This study characterizes baseline levels of serum biomarkers of ventricular wall stress, inflammation, apoptosis, neurohormonal axis activation, and extracellular matrix turnover in patients with SRCS and documents temporal changes in these levels during rapid ventricular unloading and restoration of circulation. Furthermore, because PVAD support effects ventricular unloading and restoration of circulation in a relatively stable and controllable manner, the novel experimental protocol described represents a potential opportunity to “reverse”-model the pathophysiology of cardiogenic shock.
The baseline data in this study demonstrate that patients with SRCS have markedly elevated serum levels of BNP, hsCRP, sTNFR1, endothelin-1, and PIIINP. These results would seem to validate previously published models suggesting that initial hemodynamic compromise in patients with SRCS causes downstream derangement in inflammatory, neurohormonal, and extracellular matrix remodeling pathways that may, in turn, positively feed back and worsen the degree of hemodynamic compromise (11). Interestingly, serum levels of sFas and sFasL do not appear to be elevated in patients with SRCS. These results suggest that despite significant biochemical derangement, there is not a large degree of systemic cell death occurring.
The post-PVAD data in this study suggest that ventricular unloading and restoration of circulation via PVAD support in patients with SRCS are associated with: 1) a reduction in serum BNP; 2) a reduction in serum sFas; 3) an increase in serum sFasL; 4) a reduction in serum endothelin-1; and 5) an increase in serum PIIINP levels. The BNP data parallel those from prior studies that have shown that surgically implanted VAD support was associated with reductions in left ventricular wall stress (12), left ventricular end-diastolic diameter (13), and serum BNP (14). Additionally, given prior data that an increase in serum sFas paired with a decrease in serum sFasL is a known antiapoptotic profile (15), the sFas/sFasL data parallel previous data that surgically implanted VAD support modulates myocardial gene expression compatible with a decreased susceptibility to apoptosis (16). The endothelin-1 data correlate with those in the published literature suggesting that, in a limited number of patients, surgically implanted VAD support can modulate the neurohormonal axis (17,18). Finally, the PIIINP data support those from previous studies that have demonstrated that surgically implanted VAD support can modulate biomarkers of extracellular matrix turnover, including matrix metalloproteinases, tissue inhibitors of metalloproteinases, and collagen deposition (13,19–21).
As opposed to the other serum biomarkers examined, the serum hsCRP and serum sTNFR1 data may have been influenced by both hemodynamic changes as well as the continuous contact of blood with the foreign-body surfaces of the PVAD. Prior published data in patients with cardiogenic shock receiving PVAD support have demonstrated higher fever and peak white blood cell counts compared with those in patients with cardiogenic shock receiving intra-aortic balloon pump counterpulsation (22). In that light, the statistically significant increase in hsCRP at 24 h of PVAD support demonstrated in this study could represent an acute systemic inflammatory response to the PVAD, increased tissue inflammation with restoration of adequate circulation, increased clearance of inflammatory biomarker molecules from previously poorly perfused tissue (“washout” phenomenon), or any combination of these. Similarly, the lack of a statistically significant difference between serum sTNFR1 levels at baseline compared with 24 h and 7 days of PVAD support may represent a true absence of modulation of this serum biomarker with PVAD-mediated hemodynamic changes or a “balanced” acute systemic inflammatory response to the PVAD offset by a decrease in tissue production due to restoration of circulation. Clearly, further studies are needed to better characterize the inflammatory system response in this clinical scenario.
First, the patient cohort was small. For this reason, the baseline serum biomarker medians and interquartile ranges reported simply represent estimates of such values in patients with SRCS and should not be considered definitive. Similarly, although statistical significance was achieved for a number of comparisons of serum biomarker levels between baseline and post-PVAD time points, a much larger cohort is needed to improve the external validity of these data. A larger cohort would have also enabled correlation of biomarker findings to clinical outcomes and complications of PVAD support, which was not possible in this study. The second significant limitation of this study is that many patients received blood-product transfusions between collections of serum samples and may additionally have received transfusions prior to study initiation. These transfusions may have confounded the measured concentrations of serum biomarkers.
This study demonstrates marked baseline elevation of serum BNP, hsCRP, sTNFR1, endothelin-1, and PIIINP in patients with SRCS. Additionally, this study introduces a novel PVAD-based protocol with the potential to “reverse”-model the pathophysiology of cardiogenic shock.
The authors are indebted to Dr. O. H. Frazier for his expertise and guidance. Additionally, the authors thank Ms. Dorellyn Lee for her expert advice in the laboratory. Finally, the authors thank the circulatory support staff and cardiovascular recovery nursing staff at St. Luke’s Episcopal Hospital for their support and exceptional patient care.
The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Department of the Army, or the U.S. Department of Defense. This study was funded solely by Roderick D. MacDonald research grant no. 07RDM007 awarded by St. Luke’s Episcopal Hospital, Houston, Texas. Although the Texas Heart Institute has been a training center for Cardiac-Assist, Inc. (Pittsburgh, Pennsylvania) (the manufacturer of the percutaneously implanted ventricular assist device used in this study) since 2009, all of the patients in this study were recruited prior to the establishment of this relationship. Dr. Loyalka is a consultant to St. Jude Medical and Boston Scientific; and is a proctor for St. Jude Medical for which he has received financial support. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- B-type natriuretic peptide
- high-sensitivity C-reactive protein
- procollagen III N-terminal peptide
- percutaneously implanted ventricular assist device
- soluble Fas
- soluble Fas ligand
- severe refractory cardiogenic shock
- soluble tumor necrosis factor receptor-1
- Received January 16, 2013.
- Revision received February 28, 2013.
- Accepted March 6, 2013.
- American College of Cardiology Foundation
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