C-reactive protein predicts early clinical outcomes and long-term mortality after left ventricular assisted device

Abstract

Objectives:

Left ventricular assist device (LVAD) implantation has become a reliable therapeutic strategy in patients with advanced heart failure. C-reactive protein (CRP) is a well-established biomarker of inflammation. This study aims to determine the prognostic effect of CRP level on clinical outcomes of patients who undergo LVAD implantation.

Methods:

This is a single-center, observational, retrospective study. One hundred fifty-three patients who received continuous-flow LVAD implantation were included and were divided into two groups of high (>3.9 mg/dL) versus low CRP (⩽3.9 mg/dL).

Results:

Patients with high pre-implant CRP levels were prone to severe preoperative clinical conditions and complicated intraoperative procedures. Compared with patients in the low CRP group, elevated pre-implant CRP was associated with increased hospital mortality (31.4% vs 8.4%, p < 0.001), postoperative right ventricular failure (47.1% vs 30.1%, p = 0.031), right ventricular assist device use (34.3% vs 16.9%, p = 0.013), AKI (70% vs 51.8%, p = 0.022) and significantly prolonged duration of postoperative mechanical ventilation and intensive care unit length of stay. Univariate Cox regression showed that high pre-implant CRP was significantly associated with increased risk of long-term mortality (Hazard ratio (HR) 2.632 95%; CI: 1.657–4.183, p < 0.001), and multivariable Cox regression also revealed the higher risk of long-term mortality in patients with elevated pre-implant CRP (HR, 2.848 95%CI: 1.659–4.888, p < 0.001). These results remained stable when treating pre-implant CRP as a continuous variable. Besides, the prognostic effect of post-implant CRP was also observed.

Conclusions:

CRP is a reliable risk-stratification biomarker in patients receiving continuous-flow -LVAD and can be used as a predictor for short- and long-term outcomes.

Keywords

C-reactive protein postoperative complications mortality left ventricular assist devices

Introduction

Heart failure (HF) is a growing global health problem and has become a leading cause of morbidity and mortality in patients with cardiovascular disorders. The prevalence of HF is 1% to 2% in the adult population¹ and increases strikingly in older people, with an estimated prevalence of 11.8% in people aged 60 years or older.² For patients with advanced HF, heart transplantation and left ventricular assist device (LVAD) implantation have been proposed as the definitive therapy regarding the reduction of mortality and improving quality of life (QoL).^3,4 With the severe shortage of donors’ hearts and great improvements of devices, LVAD rapidly becomes an increasing alternative therapy to heart transplantation.⁵

C-reactive protein (CRP), as a sensitive marker of both acute and chronic inflammation, could rise robustly and rapidly in response to tissue damage and inflammation. CRP level is routinely monitored in hospitalized patients to assess the severity of initial illness and efficacy of therapeutic interventions.⁶ Elevated CRP is recognized as an independent marker and predictor of cardiovascular diseases in the healthy population and an increased risk of cardiovascular events in patients with cardiovascular disease (CVD).^6–8 Elevated pre-implant CRP levels are also associated with increased postoperative complications, hospital length of stay (HLOS), all-cause death, and long-term mortality in patients after various cardiovascular interventions.^9–12 Besides, in patients with HF, high CRP levels correlate with more severe symptoms and are independently associated with increased mortality and morbidity.¹³

A recent study demonstrated that pre-implant CRP could predict postoperative complications and mortality in patients with LVAD support.¹⁴ However, the effect of CRP on perioperative outcomes and postoperative complications is lacking. Therefore, we sought to determine the effect of CRP on perioperative outcomes, postoperative complications, and long-term mortality in patients after continuous-flow LVAD implantation.

Materials and methods

Study population

The Institutional Review Committee approved this single-institution, observational, retrospective cohort study, and written patient consent was waived. Consecutive adult patients who underwent continuous-flow LVAD implantation (HeartMate II, HeartWare, and HeartMate 3) between January 2009 and February 2020 were evaluated for inclusion.

Data collection

Preoperative variables, operative variables, main etiology of heart failure (ischemic cardiomyopathy (ICM), dilatative cardiomyopathy (DCM), and others), and follow-up data were collected retrospectively. Patients’ comorbidities, previous cardiac surgery, and laboratory examinations were extracted from the clinical information system. Quantitative measurement of (non-high-sensitivity) plasma CRP levels before the operation was routinely performed. CRP levels less than the sensitivity threshold of 0.5 mg/dL were regarded as normal, and these values were recorded as a value half of the detection threshold when CRP was analyzed as a continuous variable.

Definitions of outcomes

Perioperative outcomes included the duration of cardiopulmonary bypass, the incidence of concurrent right ventricular assist device (RVAD) implantation, operation time, and aortic clamp time. Postoperative right ventricular failure (RVF) was diagnosed if post-implant inotropes, inhaled nitric oxide, or intravenous vasodilators were administered continuously beyond 1 week after LVAD implantation or if the implantation of a RVAD was required. AKI was determined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria based on changes in serum creatine.¹⁵ Survival data were obtained from our single-center LVAD follow-up database, and the endpoint was defined as death. Other outcomes include hospital mortality, RVAD use, new-onset renal replacement therapy (RRT), postoperative duration of RVAD support, postoperative duration of mechanical ventilation (MV) time, postoperative intensive care unit length of stay, and postoperative HLOS were extracted from the clinical information system.

Statistical analysis

The cut-off value for pre-implant and post-implant CRPs was determined by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data with a nearest neighbor estimation methods, and this calculation was performed in R software (version 4.0.2) with the survivalROC package (Version 1.0.3, Heagerty and Saha-Chaudhuri).¹⁶ Continuous variables were expressed as mean ± standard deviation (SD) for normally distributed data or median with interquartile range (IQR) for non-normal distributed data, and independent t-test or Mann-Whitney U tests were used for the comparison between the subgroups. Categorical variables were compared with chi-square or Fisher’s exact test when appropriate. ROC curves were used to evaluate the predictive accuracy of pre-implant CRP. Kaplan–Meier curves with 95% confidence intervals (CI) were used, and the difference between the two groups was compared by log-rank test. Besides, a multivariable Cox regression was performed to estimate the adjusted hazard ratios (HRs) for post-LVAD mortality by incorporating potential predictors identified from univariate Cox regression (inclusion criteria of two-tailed p < 0.05). Besides, the effect of CRP at post-implant 7 days on long-term survival was also investigated by Kaplan–Meier curves and univariate Cox regression. All statistical analyses were performed using SPSS Statistics 26.0 (IBM, Armonk, NY, USA).

Results

Study population

177 adult patients were evaluated for inclusion, and patients who received two LVAD as durable BiVAD support (n = 2), LVAD revisions because of LVAD thrombus or LVAD dysfunction (n = 8), oHTx before LVAD (n = 1), and patients with no pre-implant CRP data (n = 13) were excluded. Finally, a total of 153 patients were included for the final analysis and divided into two groups in terms of high (>3.9 mg/dL) vs low CRP (⩽3.9 mg/dL), according to the cutoff canulated from time-dependent ROC analysis.

Baseline characteristics

The median CRP level of the overall 153 patients was 3.3 mg/dL ([IQR] 1.25 mg/dL to 7.9 mg/dL). The distributions of CRP and log-transformed CRP values are shown in Figure 1, and the baseline characteristic and pre-implant variables are presented in Table 1. Patients with high pre-implant CRP were likely to belong to Intermacs I–II levels. They also had higher prevalences of acute myocardial infarct, hyperuricemia, cardiac arrest, prior coronary artery bypass grafting (CABG), mechanical circulation support, and lower prevalences of dyslipidemia and prior ICD implantation. The laboratory results are summarized in Supplemental Table S1. High pre-implant CRP was associated with increased alanine aminotransferase, lactate dehydrogenase, white blood cells, and reduced red blood cells, hemoglobin, hematocrit, and platelets. The intraoperative variables and outcomes are summarized in Table 2. Compared with patients in the low CRP group, patients with high pre-implant CRP were more likely to undergo median sternotomy for LVAD implantation and extracorporeal membrane oxygenation for extracorporeal life support.

Figure 1.

The distributions of CRP (a) and log-transformed CRP values (b).

Table 1.

Baseline characteristics between the high and low pre-implant CRP in patients after continuous-flow LVAD.

Variables	Overall (n = 153)	Lower CRP (n = 83)	Higher CRP (n = 70)	p
Age (years)	56 (47–63)	57 (47–63)	54.5 (44–63)	0.691
Male	118 (77.1)	68 (81.9)	50 (71.4)	0.123
Weight	80.5 (70-93)	80.5 (68-93)	81 (70-93)	0.946
BMI	26.65 ± 4.75	26.34 ± 4.42	27.0 ± 5.12	0.394
LVAD Indication
BTT	80 (50.3)	43 (51.8)	37 (52.9)	0.996
BTR	4 (2.6)	2 (2.4)	2 (2.9)
BTD	22 (14.4)	12 (14.5)	10 (14.3)
DT	47 (30.7)	26 (31.3)	21 (30.0)
INTERMACS, N (%
I–II	79 (51.6)	26 (31.3)	53 (75.7)	<0.001
III–V	74 (48.4)	57 (68.7)	17 (24.3)	<0.001
Main Cardiac disease
DCM	78 (51.0)	45 (54.2)	33 (47.1)	0.235
ICM	67 (43.8)	32 (38.6)	35 (50.0)
Others	8 (5.2)	6 (7.2)	2 (2.9)
Coronary artery disease	82 (53.6)	41 (49.4)	41 (58.6)	0.257
Diabetes mellitus	30 (19.6)	21 (25.3)	9 (12.9)	0.053
Acute myocardial infract	18 (11.8)	5 (6.0)	13 (18.6)	0.016
Hypertension	92 (60.1)	54 (65.1)	38 (54.3)	0.175
Dyslipidemia	73 (47.7)	47 (56.6)	26 (37.1)	0.016
Renal disease	74 (48.7)	39 (47.0)	35 (50.0)	0.710
Hyperuricemia	31 (20.3)	26 (31.3)	5 (7.1)	<0.001
Obesity	39 (25.5)	19 (22.9)	20 (28.6)	0.422
Cardiac arrest	24 (15.7)	6 (7.2)	18 (25.7)	0.002
Ventricular tachycardia	48 (31.4)	24 (28.9)	24 (34.3)	0.476
Atrial fibrillation	82 (53.6)	45 (54.2)	37 (52.9)	0.867
Prior ICD implantation	84 (54.9)	54 (65.1)	30 (42.9)	0.006
Prior CABG	30 (19.6)	11 (13.3)	19 (27.1)	0.031
Prior Valve surgery	12 (7.8)	5 (6.09	7 (10.0)	0.362
Prior Stenting	40 (26.1)	23 (27.7)	17 (24.3)	0.631
Mechanical support before LVAD	43 (28.1)	7 (8.4)	36 (51.4)	<0.001

CRP: C-reactive protein; LVAD: left ventricular assist device; BMI: body mass index; BTT: bridge to transplantation; BTR: bridge to recovery; BTD: bridge to decision; DT: destination therapy; INTERMACS: Interagency Registry of Mechanically Assisted Circulatory Support; DCM: dilated cardiomyopathy; ICM: Ischemic cardiomyopathy; ICD: implantable cardioverter-defibrillator; CABG: coronary artery bypass grafting.

Continuous data are expressed as mean ± SD or Median and interquarter (25th and 75th).

Table 2.

Peri-operative characteristics and outcomes between high and low pre-implant CRP groups in patients after continuous flow-LVAD.

Variables	Overall (n = 153)	Lower CRP (n = 83)	Higher CRP (n = 70)	p
Peri-operative variable
Device
HeartMate II	32 (20.9)	16 (19.3)	16 (22.9)	0.442
HeartWare	95 (62.1)	50 (60.2)	45 (64.3)
HeartMate 3	26 (17)	17 (20.5)	9 (12.9)
Surgical access
mSTE	120 (78.4)	59 (71.1)	61 (87.1)	0.025
puSTE	30 (19.6)	23 (27.7)	7 (10)
ALT	1 (0.7)	0	1 (1.4)
ALT+puSTE	2 (1.3)	1 (1.2)	1 (1.4)
ECLS
ECMO	16 (10.5)	1 (1.2)	15 (21.4)	<0,001
HLM	137 (89.5)	82 (98.8)	55 (78.6)	<0,001
Post-CABG heart failure-LVAD	11 (7.2)	3 (3.6)	8 (11.4)	0.062
Concurrent cardiac surgery
TVS	50 (32.7)	30 (36.1)	20 (28.6)	0.320
CABG	2 (1.3)	1 (1.2)	1 (1.4)	1.000
AVS	3 (2.0)	1 (1.2)	2 (2.9)	0.593
ASD closure	6 (3.9)	1 (1.2)	5 (7.1)	0.094
Peri-operative outcomes
Duration of HLM support (mins)	224 (180.5-259.75)	199 (175-245)	235 (196.5-270)	0.015
Surgical time (mins)	116 (80.5-141.5)	107 (80-137)	123 (84-145)	0.165
Aortic clamp time (mins)	50 (38.25-70.75)	46 (36.75-66.5)	54 (40.75-76)	0.180
RVAD implantation	32 (20.9)	12 (14.5)	20 (28.6)	0.032

CRP: C-reactive protein; LVAD: left ventricular assist device; mSTE: median sternotomy; puSTE: partial upper sternotomy; ALT: anterolateral thoracotomy; ECLS: extracorporeal life support; ECMO: extracorporeal membrane oxygenation; HLM: heart-lung machine; CABG: coronary artery bypass grafting; TVS: tricuspid valve surgery; AVS: aortic valve surgery; ASD: atrial septal defect; RVAD, right ventricular assist device.

Continuous data are expressed as mean ± SD or Median and interquarter (25th and 75th).

Association of pre-implant CRP with perioperative outcomes

As shown in Table 2, high pre-implant CRP was correlated with a significantly longer duration of cardiopulmonary bypass [235 (196.5–270) vs 199 (175–245), p = 0.015] and increased incidence of concurrent RVAD implantation (28.6% vs 14.5%, p = 0.032). No difference in operation time and aortic clamp time was observed.

Association of pre-implant CRP with postoperative outcomes

Table 3 shows postoperative outcomes. Patients with high pre-implant CRP had significantly increased hospital mortality (31.4% vs 8.4%, p < 0.001) and incidences of postoperative RVF (47.1% vs 30.1%, p = 0.031), RVAD implantation (34.3% vs 16.9%, p = 0.013), and postoperative AKI (70% vs 51.8%, p = 0.022) compared to patients in the low CRP group. ROC curves showed that pre-implant CRP could accurately predict hospital mortality, RVAD implantation, and postoperative AKI, with AUCs of 0.688, 0.623, and 0.623, respectively (Figure 2). Besides, a high pre-implant CRP level was associated with remarkably prolonged postoperative duration of MV and postoperative intensive care unit (ICU) length of stay, and the results remained stable when only including patients who were successfully discharged. No significant differences were detected between groups regarding the incidence of new-onset RRT, re-ICU admission, re-admission within 30 days, duration of RVAD support, and postoperative HLOS.

Table 3.

Postoperative outcomes between the high and low pre-implant CRP groups in patients after continuous-flow LVAD.

Postoperative outcomes	Overall	Lower CRP	Higher CRP	p
All patients	153	83	70
Hospital mortality	29 (19.0)	7 (8.4)	22 (31.4)	<0.001
Postoperative RVF	58 (37.9)	25 (30.1)	33 (47.1)	0.031
RVAD used (including post- and peri-OP)	38 (24.8)	14 (16.9)	24 (34.3)	0.013
RVAD used (post-OP)	6 (3.9)	2 (2.4)	4 (5.7)	0.413
AKI	92 (60.1)	43 (51.8)	49 (70.0)	0.022
Stage 1	43 (28.1)	24 (28.9)	19 (27.1)	0.808
Stage 2	14 (9.2)	1 (1.2)	13 (18.6)	<0.001
Stage 3	35 (22.9)	18 (21.7)	17 (24.3)	0.703
New onset of CRRT AKI	27 (17.6)	17 (20.5)	10 (14.3)	0.317
New onset of CRRT all	48 (31.4)	26 (31.3)	22 (31.4)	0.989
Postoperative duration of MV (hours)	122 (39–420)	71.5 (28–271.3)	306 (70.5–542)	<0.001
Postoperative duration of ICU stays (days)	19 (10–49)	14 (8–32)	31 (14–55.3)	<0.001
Postoperative HLOS (days)	55 (35.5–83.5)	53 (33–78)	57.5 (37.3–98.3)	0.430
Patients with RVAD	38	14	24
Duration RVAD duration (days)	12.5 (6–19.3)	15.5 (7.8–21.3)	11.5 (6–14.8)	0.191
Patients successfully weaned RVAD	26	11	15
Duration of RVAD support (days)	11.5 (6–20.75)	12 (7–20)	11 (6–23)	0.838
Patients successfully discharged from 1st ICU	126	75	51
Re-ICU admission	36 (28.6)	21 (28)	15 (29.4)	0.863
Patients successfully discharged	119	73	46
Re-admission with 30 days	35 (29.4)	25 (34.2)	10 (21.7)	0.145
Postoperative duration of MV (hours)	79 (33.5–346)	65 (28–225.8)	171 (53–488.5)	0.005
Postoperative duration of ICU stays (days)	18 (9–46)	14 (7.3–31.5)	32 (14.5–53)	0.001
Postoperative HLOS (days)	58 (41–88)	55 (39.3–82.8)	67 (45–109.5)	0.075

CRP: C-reactive protein; LVAD: left ventricular assist device; RVAD: right ventricular assist device; AKI: acute kidney disease; RRT: renal replacement therapy; MV: mechanical ventilation; ICU: intensive care unit; HLOS: hospital length of stay.

Figure 2.

ROC curves for pre-implant CRP to predict (a) hospital mortality, (b) RVAD use, and (c) AKI in patients after CF-LVAD.

Association of pre-implant CRP with long-term mortality

During a median follow-up of 1401 days (IQR 1092 days to 1709 days), 77 died on LVAD, 30 received heart transplantations. Four patients were weaned from LVADs, two were lost to follow-up, and 40 were still alive with LVAD support. Kaplan–Meier survival analysis showed that patients with a high pre-implant CRP had lower survival than patients with low pre-implant CRP (Figure 3, Log-rank p < 0.001). As shown in Table 4, univariate Cox regression shows that high pre-implant CRP was significantly associated with increased risk of long-term mortality (HR 2.632 95%CI: 1.657 to 4.183, p < 0.001). In patients with high baseline CRP, the multivariable HR for long-term mortality was 2.848 (95%CI: 1.659-4.888, p < 0.001) by comparison of patients with low pre-implant CRP. Consistently, when CRP was defined as a continuous variable, the multivariable results also revealed that log-transformed pre-implant CRP correlated positively with mortality in patients after LVAD (HR 1.812 95%CI: 1.027-3.197, p = 0.040).

Figure 3.

Kaplan–Meier survival curves for the high and low pre-implant CRP on long-term mortality.

Table 4.

Multivariable Cox regression analysis for pre-implant CRP on long-term mortality after continuous-flow LVAD.

Variables	Univariate COX	p	Multivariable COX (Continuous)	p	Multivariable COX (Dichotomous)	p
Age	1.035 (1.015–1.056)	0.001	1.033 (1.007–1.061)	0.014	1.036 (1.009–1.063)	0.008
Coronary artery disease (Yes vs No)	1.602 (1.010–2.541)	0.045	1.070 (0.565–2.025)	0.835	0.921 (0.485–1.747)	0.800
Dyslipidemia (Yes vs No)	1.582 (1.009–2.483)	0.046	1.497 (0.826–2.712)	0.183	1.762 (0.976–3.182)	0.060
Obesity (Yes vs. No)	1.665 (1.021–2.714)	0.041	1.745 (0.960–3.170)	0.068	1.732 (0.955–3.141)	0.071
Prior Valve surgery (Yes vs. No)	2.105 (1.043–4.251)	0.038	1.210 (0.508–2.880)	0.666	1.073 (0.459–2.509)	0.871
ECLS (ECMO vs HLM)	1.385 (1.027–1.867)	0.033	–		–
Duration of HLM support (mins)	1.011 (1.006–1.017)	<0.001	1.014 (1.003–1.025)	0.011	1.013 (1.003–1.024)	0.015
Surgical time (mins)	1.004 (1.001–1.007)	0.003	0.997 (0.991–1.004)	0.420	0.998 (0.991–1.004)	0.492
RVAD implantation (Yes vs No)	1.849 (1.141–2.995)	0.013	1.657 (0.841–3.263)	0.144	1.398 (0.715–2.733)	0.328
Pre-implant CRP (High vs Low)	2.632 (1.657–4.183)	<0.001	–		2.848 (1.659–4.888)	<0.001
Log-transformed CRP (continuous)	1.776 (1.124–2.806)	0.014	1.812 (1.027–3.197)	0.040	–

CRP: C-reactive protein; LVAD: left ventricular assist device; ECLS: extracorporeal life support; ECMO: extracorporeal membrane oxygenation; HLM: heart-lung machine.

Association of post-implant CRP with long-term mortality

Supplemental Figure S1a shows the CRP change from pre-implant to 7 days after LVAD implantation, and there was a peak of post-implant CRP at 3 days after LVAD implantation (18.04 ± 8.37 mg/dL). Since the CRP level became relatively stable at 7 days after implantation, we further investigate the association of post-implant 7-day CRP with long-term mortality. A total of 143 patients were involved, and the cut-off value for post-implant CRP identified by using time-dependent ROC analysis was 13.3 mg/dL. As shown in Supplemental Figure S1b, patients with a high post-implant CRP (⩾13.3 mg/dL) had a poor survival compared to patients with a low post-implant CRP, with a log-rank p value of 0.015. Univariate Cox regression showed that high post-implant CRP was also associated with increased risk of long-term mortality (HR 1.788 95%CI: 1.111–2.878, p = 0.017).

Discussion

Our study showed that high CRP was associated with a more severe clinical condition before LVAD implantation, indicated by INTERMACS I-II level, higher MCS support, more comorbidities, and abnormal lab results. Secondly, elevated pre-implant CRP was associated with an increased incidence of RVAD implantation. In addition, elevated CRP was associated with increased risks of hospital mortality, postoperative RVF, RVAD use, AKI, and significantly prolonged duration of mechanical ventilation and ICU length of stay. Furthermore, high pre-implant and post-implant CRP was a significant independent predictor for long-term mortality. These findings suggest that pre-implant CRP is a good biomarker for identifying high-risk patients and predicting poor clinical outcomes.

Pulmonary hypertension and ventricular structural abnormality are important contributors to RVF. Previous studies showed that circulating CRP was independently associated with abnormal right ventricular structural changes¹⁷ and poor clinical outcomes, especially in patients with pulmonary hypertension.¹⁸ Our study also confirms that patients with elevated pre-implant CRP had a poor right ventricular function, as indicated by higher incidences of postoperative RVF and RVAD support use. Since heart and kidney communicate with one another through an intricate network to maintain hemodynamic stability and organ perfusion, AKI usually occurs in patients after cardiac surgery or with HF. In patients after LVAD implantation, the incidence of AKI was considerably high, with a range of 10% to 70%. Cosentino et al.¹⁹ reported that high-sensitivity CRP (hs-CRP) was closely associated with AKI development and severity in acute myocardial infarction patients. A retrospective cohort study with 1656 patients undergoing CABG showed that pre-implant CRP is a predictor of postoperative AKI.²⁰ Another study conducted in non-cardiac surgical patients indicated that the pre-implant CRP levels were also significantly related to postoperative AKI.²¹ Though plenty of evidence exists in various settings, including cardiac and non-cardiac surgeries, no previous study investigated the relationship between pre-implant CRP and postoperative AKI in a specific group of patients who received LVAD. Our study found that AKI occurred in 60.1% of patients undergoing continuous-flow LVAD and it was significantly related to high pre-implant CRP.

Consistent with findings of CRP in other settings,^22–24 high pre-implant CRP was associated with increased hospital mortality in patients after LVAD. Besides, the current study indicated that both pre-implant and post-implant CRP is significant predictor of long-term mortality following LVAD implantation. With a longer-time analysis, we shared a similar finding to a previous study with 24 months follow-up.¹⁴ Besides, the significantly prolonged duration of MV, ICU stay, and hospital stay identified in our study also evidenced the poor prognostic factor of pre-implant CRP. Moreover, we also found that high CRP at 7 days after LVAD implantation was also associated with an increased risk of long-term mortality. Taken together, our study reinforced the previous findings by adding more complications and a longer median follow-up of 46 months.

The mechanism between CRP and mortality as well as postoperative complications is still not clear. CRP is well acknowledged as an inflammatory biomarker, and its production is especially stimulated via an upstream proinflammatory cytokine-dependent hepatic biosynthesis.²⁵ Elevated CRP was usually seen in severely ill patients and considered as a biomarker for an active infection. The severe systematic inflammatory response in such patients is usually related to worse clinical outcomes. However, accumulating studies suggested that neither IL-6 nor CRP only indicated inflammation but were also mediators participating in different signal pathways.²⁶ Systemic inflammation participates in right ventricular structural changes independent of its effect on the left ventricle.¹⁷ Though the potential mechanisms are still unclear, myocardial nitric oxide synthase-mediated negative inotropic effects of IL-6 might be involved.²⁷ Inflammation also plays a critical role among all those common causes for AKI.²⁸ It has been demonstrated that pre-implant CRP contributes to endothelial dysfunction and reduced response to renal vasodilators by promoting coagulation activity and inhibiting nitric oxide production.^29,30 Other than inflammation, potential mechanisms of CRP on cardiac function and poor clinical outcomes in patients receiving LVAD need to be further clarified.

The results of our study support the use of CRP as a risk-stratification tool to select high-risk patients. Besides, the relationship between CRP level and postoperative complications such as RVF and AKI may help clinicians to evaluate the severity of patients and assist the decision-making process. Future multi-center, large sample-size studies with long-term follow-up regarding the medical and socio-economic effects of CRP-guided interventions may be helpful. Since hsCRP is more sensitive to be quantified with a low detect threshold,³¹ it might act as a more valuable biomarker than CRP in the clinical risk-stratification and prognostic prediction model.

Several limitations exist in the present study. Firstly, our study is a single-center, retrospective cohort study, and the bias because of the study design limits to derive a causal relationship and may include some unidentified confounders. While our results are consistent with a recent large multi-center cohort study using registry data, our study strengthens and expands current evidence with more outcomes and longer follow-up. Secondly, the kinetics of CRP levels and their effect during the follow-up were not tracked. Given that the current study aims to investigate the predictive effect of CRP, the results show that CRP is sufficient to select high-risk patients and predict short and long-term outcomes. Thirdly, though a CRP cut-off of 3.9 mg/dL calculated from ROC analysis could predict poor outcomes in patients after LVAD, the appropriate cut-off remains uncertain and needs further exploration.

Conclusion

In summary, CRP is a comprehensive biomarker of severe clinical presentation before LVAD implantation and a predictor for postoperative complications and long-term mortality. These findings suggest that CRP should be integrated into patients’ risk stratification before LVAD implantation and the prognostic model after LVAD.

Supplemental Material

sj-pdf-1-jao-10.1177_03913988221088614 – Supplemental material for C-reactive protein predicts early clinical outcomes and long-term mortality after left ventricular assisted device

Supplemental material, sj-pdf-1-jao-10.1177_03913988221088614 for C-reactive protein predicts early clinical outcomes and long-term mortality after left ventricular assisted device by Hongtao Tie, Rui Shi, Henryk Welp, Sven Martens, Zhenhan Li, Jürgen Sindermann and Sabrina Martens in The International Journal of Artificial Organs

Supplemental Material

sj-tif-2-jao-10.1177_03913988221088614 – Supplemental material for C-reactive protein predicts early clinical outcomes and long-term mortality after left ventricular assisted device

Supplemental material, sj-tif-2-jao-10.1177_03913988221088614 for C-reactive protein predicts early clinical outcomes and long-term mortality after left ventricular assisted device by Hongtao Tie, Rui Shi, Henryk Welp, Sven Martens, Zhenhan Li, Jürgen Sindermann and Sabrina Martens in The International Journal of Artificial Organs

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Hongtao Tie

Sabrina Martens

Supplemental material

Supplemental material for this article is available online.

References

Groenewegen

Rutten

Mosterd

, et al. Epidemiology of heart failure. Eur J Heart Fail 2020; 22: 1342–1356.

van Riet

Hoes

Wagenaar

, et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time: a systematic Review. Eur J Heart Fail 2016; 18: 242–252.

Bayes-Genis

Muñoz-Guijosa

Santiago-Vacas

, et al. Destination therapy with left ventricular assist devices in non-transplant centres: the time is right. Eur Cardiol 2020; 15: e19.

Miller

Birks

Guglin

, et al. Use of ventricular assist devices and heart transplantation for advanced heart failure. Circ Res 2019; 124: 1658–1678.

Molina

Shah

Kiernan

, et al. The society of thoracic surgeons intermacs 2020 annual report. Ann Thorac Surg 2021; 111: 778–792.

Jimenez

Szalai

. Therapeutic lowering of c-reactive protein. Front Immunol 2020; 11: 619564.

Nelson Adam

Nicholls

Lincoff

, et al. Elevated levels of the neutrophil to lymphocyte ratio predicts incidence of major adverse cardiovascular events in high risk patients: insights from accelerate. J Am Coll Cardiol 2018; 71: A33–A33.

Singh

Morris

Smith

, et al. Systematic review and meta-analysis of the association between c-reactive protein and major cardiovascular events in patients with peripheral artery disease. Eur J Vasc Endovasc Surg 2017; 54: 220–233.

Hioki

Watanabe

Kozuma

, et al. Effect of serum C-reactive protein level on admission to predict mortality after transcatheter aortic valve implantation. Am J Cardiol 2018; 122: 294–301.

10.

Perry

Muehlschlegel

Liu

, et al. Preoperative C-reactive protein predicts long-term mortality and hospital length of stay after primary, nonemergent coronary artery bypass grafting. Anesthesiology 2010; 112: 607–613.

11.

Takagi

Kuno

Hari

, et al. Prognostic impact of baseline C-reactive protein levels on mortality after transcatheter aortic valve implantation. J Card Surg 2020; 35: 974–980.

12.

Park

Lee

Yun

, et al. Prognostic impact of preprocedural C reactive protein levels on 6-month angiographic and 1-year clinical outcomes after drug-eluting stent implantation. Heart 2007; 93: 1087–1092.

13.

Anand

Latini

Florea

, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation 2005; 112: 1428–1434.

14.

Batra

Truby

Defilippis

, et al. C-reactive protein levels predict outcomes in continuous-flow left ventricular assist device patients: an INTERMACS analysis. Asaio J 2021; 67: 884–890.

15.

Yalcin

Bunge

JJH

Guven

, et al. Acute kidney injury following left ventricular assist device implantation: contemporary insights and future perspectives. J Heart Lung Transplant 2019; 38: 797–805.

16.

Heagerty

Lumley

Pepe

. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics 2000; 56: 337–344.

17.

Harhay

Tracy

Bagiella

, et al. Relationship of CRP, IL-6, and fibrinogen with right ventricular structure and function: the MESA-Right Ventricle Study. Int J Cardiol 2013; 168: 3818–3824.

18.

Sztrymf

Souza

Bertoletti

, et al. Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension. Eur Respir J 2010; 35: 1286–1293.

19.

Cosentino

Genovese

Campodonico

, et al. High-sensitivity C-reactive protein and acute kidney injury in patients with acute myocardial infarction: a prospective observational study. J Clin Med 2019; 8: 2192.

20.

Han

Kim

, et al. C-reactive protein predicts acute kidney injury and death after coronary artery bypass grafting. Ann Thorac Surg 2017; 104: 804–810.

21.

Murashima

Nishimoto

Kokubu

, et al. Inflammation as a predictor of acute kidney injury and mediator of higher mortality after acute kidney injury in non-cardiac surgery. Scientific Reports 2019; 9: 1–9.

22.

Ullah

Thalambedu

Haq

, et al. Predictability of CRP and D-Dimer levels for in-hospital outcomes and mortality of COVID-19. J Community Hosp Intern Med Perspect 2020; 10: 402–408.

23.

Qian

Wang

, et al. Prediction of 10-year mortality using hs-CRP in Chinese people with hyperglycemia: findings from the Da Qing diabetes prevention outcomes study. Diabetes Res Clin Pract 2021; 173: 108668.

24.

Goldberg

Shalmon

Shteinvil

, et al. The superiority of 72 h leukocyte descent over CRP for mortality prediction in patients with sepsis. Clin Chim Acta 2021; 514: 34–39.

25.

Eklund

. Proinflammatory cytokines in CRP baseline regulation. Adv Clin Chem 2009; 48: 111–136.

26.

Del Giudice

Gangestad

. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun 2018; 70: 61–75.

27.

Finkel

Oddis

Jacob

, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 387–389.

28.

Bruins

te Velthuis

Yazdanbakhsh

, et al. Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation 1997; 96: 3542–3548.

29.

Fujii

Szmitko

, et al. C-reactive protein alters antioxidant defenses and promotes apoptosis in endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2006; 26: 2476–2482.

30.

Cermak

Key

Bach

, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82: 513–520.

31.

Koosha

Roohafza

Sarrafzadegan

, et al. High sensitivity C-reactive protein predictive value for cardiovascular disease: a nested case control from Isfahan cohort study (ICS). Glob Heart 2020; 15: 3.

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