European Journal of Heart Failure (2014) 16, 758–766 doi:10.1002/ejhf.104
C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction L. Koller1†, M. Kleber2†, G. Goliasch1,3, P. Sulzgruber1, H. Scharnagl4, G. Silbernagel5, T. Grammer2,6, G. Delgado2, A. Tomaschitz7,8, S. Pilz9, W. März2,4,10, and A. Niessner1* 1 Division
of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Austria; 2 Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; 3 Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA; 4 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; 5 Department of Angiology, Inselspital, Bern, Switzerland; 6 Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Germany; 7 Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee, Bad Aussee, Austria; 8 Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria; 9 Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria; and 10 Synlab Academy, Synlab Services GmbH, Mannheim, Germany Received 14 January 2014; revised 14 March 2014; accepted 21 March 2014 ; online publish-ahead-of-print 7 May 2014
Aims
Heart failure with preserved ejection fraction (HFpEF) has a different pathophysiological background compared to heart failure with reduced ejection fraction (HFrEF). Tailored risk prediction in this separate heart failure group with a high mortality rate is of major importance. Inflammation may play an important role in the pathogenesis of HFpEF because of its significant contribution to myocardial fibrosis. We therefore aimed to assess the predictive value of C-reactive protein (CRP) in patients with HFpEF. ..................................................................................................................................................................... Methods Plasma levels of CRP were determined in 459 patients with HFpEF in the LUdwigshafen Risk and Cardiovascular and results Health (LURIC) study using a high-sensitivity assay. During a median follow-up of 9.7 years 40% of these patients died. CRP predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.20 [95% confidence interval (CI) 1.02–1.40, P = 0.018] and cardiovascular mortality with a HR of 1.32 (95% CI 1.08–1.62, P = 0.005) per increase of one standard deviation. CRP was a significantly stronger mortality predictor in HFpEF patients than in a control group of 522 HFrEF patients (for interaction, P = 0.015). Furthermore, CRP added prognostic value to N-terminal pro B-type natriuretic peptide (Nt-proBNP): the lowest 5-year mortality rate of 6.8% was observed for patients in the lowest tertile of Nt-proBNP as well as CRP. The mortality risk peaked in the group combining the highest values of Nt-proBNP and CRP with a 5-year rate of 36.5%. ..................................................................................................................................................................... Conclusion It was found that CRP was an independent and strong predictor of mortality in HFpEF. This observation may reflect immunological processes with an adverse impact on the course of HFpEF.
.......................................................................................................... Keywords
Biomarker • Inflammation
Heart failure with preserved ejection fraction •
High-sensitivity C-reactive protein •
*Corresponding author. Tel: +43 1404004614, Fax: +43 1404004216, Email: [email protected] † These authors contributed equally to this work.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Introduction During the last decades heart failure (HF) with preserved ejection fraction (HFpEF) was identified as a distinct entity of HF with different pathophysiology and patient characteristics compared with HF with reduced ejection fraction (HFrEF).1 – 3 Therefore, targeted risk prediction is of utmost importance in this group of patients with relatively high risk of fatal and non-fatal cardiovascular events.4 Activation of the immune system has been shown to be crucially implicated in chronic HF.5 More precisely, high plasma concentrations of several pro-inflammatory cytokines are closely linked with disease progression and poor prognosis.6 However, most studies addressing immunological processes in HF have been performed in patients with HFrEF, while evidence about inflammatory processes in the pathophysiology of HFpEF is relatively scarce.7,8 It has been determined that C-reactive protein (CRP) is one of the most promising markers for risk assessment in clinical practice and is therefore recommended for risk stratification in the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guidelines for Assessment of Cardiovascular Risk in Asymptomatic Adults.9 CRP, an acute-phase reactant predominantly released from hepatocytes, is a non-specific inflammatory marker clearly associated with adverse cardiovascular disease (CVD) outcomes.10 While CRP has been examined in large epidemiological studies, and in a variety of clinical settings including patients with HFrEF, only scarce data are available in patients with HFpEF.11 – 13 Based on the pathophysiological role of inflammation in cardiovascular diseases and its association with fibrosis we hypothesized that CRP may be a useful marker for refining risk prediction in HFpEF patients with underlying myocardial fibrosis. Therefore, we assessed the predictive power of CRP in a prospective registry including 459 patients presenting with HFpEF. In addition to the impact of CRP on mortality, we specifically focused on the gain in risk prediction beyond N-terminal pro B-type natriuretic peptide (Nt-proBNP), which is currently the most important biomarker in HF risk assessment.
Methods Study population Patients included in this analysis were participants of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. The detailed study protocol has been described previously.14 In brief, 3316 patients referred to the Heart Centre of Ludwigshafen for coronary angiography were enrolled between July 1997 and January 2000. To address the study goals, we identified 506 patients with HFpEF in a stable condition according to current recommendations of the Heart Failure and Echocardiography Associations of the European Society of Cardiology.15 After exclusion of acute or chronic infection, autoimmune diseases and cancer, the final patient cohort comprised 459 patients. All patients with the following characteristics were included: symptoms and signs of HF, a preserved left ventricular function with an ejection fraction >45% (echocardiographic or invasive) and the presence of diastolic HF according to the definition published by Paulus et al.15 In particular, diastolic dysfunction was diagnosed in 388 patients (85%) based on haemodynamic criteria (mean pulmonary
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CRP predicts mortality in patients referred for coronary angiography and HFpEF
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
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capillary wedge pressure >12 mmHg or a left ventricular end-diastolic pressure >16 mmHg). In the remaining 71 patients (15%) diastolic dysfunction was identified by an elevated Nt-proBNP concentration (>220 pg/mL) and electrocardiographic evidence of atrial fibrillation. Written informed consent was obtained from all study participants. The LURIC study complies with the Declaration of Helsinki and was approved by the Ethics Committee of the ‘Landesärztekammer Rheinland-Pfalz’ (Mainz, Germany).
Follow-up and study endpoints All-cause and cardiovascular mortality were chosen as primary study endpoints and were obtained by browsing local community registries, including revision of death certificates to classify these into cardiovascular and non-cardiovascular causes of death, as previously described.16 Cardiovascular mortality included fatal myocardial infarction, sudden cardiac death, death after cardiovascular intervention, stroke and other causes of death resulting from cardiac diseases. A sample size of 460 patients with 40% of patients experiencing the primary endpoint enabled detection of a risk ratio of 1.5 between 1st and 3rd tertile (𝛼 = 0.05, power = 80%).
Blood sampling and laboratory analyses Venous blood samples were taken at study enrolment in the supine position. Routine laboratory parameters were analysed according to local laboratory standard procedures. For the measurement of further biomarkers ethylenediaminetetraacetic acid (EDTA) plasma samples were snap frozen at −80∘ C after centrifugation (1825 g, 20 min) and stored until analysis. The CRP concentrations were measured using high-sensitivity immunonephelometry (Dade Behring, Marburg, Germany). Interassay and intra-assay CVs were 55%, n (%) 45–55%, n (%) Left ventricular end-diastolic pressure ≤16 mmHg, n (%) >16 mmHg, n (%) Pulmonary wedge capillary pressure ≤12 mmHg, n (%) >12 mmHg, n (%) Atrial fibrillation, n (%)
3.88 (1.36–9.37)
1.00 (0.69–1.37)
3.88 (2.59–5.42)
13.8 (9.3–3.35)
99 (21.5) 13 (2.8)
16 (10.5) 2 (1.3)
37 (24.2) 6 (3.9)
46 (30.1) 5 (3.3)
64 (14.4) 241 (54.0) 141 (31.6) 533 (245–1306)
29 (19.1) 85 (55.9) 37 (24.3) 434 (179–857)
21 (14.7) 73 (51.0) 49 (34.4) 534 (246–1583)
12 (8.2) 81 (55.1) 54 (36.7) 748 (300–1662)
310 (70.3) 131 (29.7)
110 (74.3) 38 (25.7)
107 (72.3) 41 (27.7)
92 (63.9) 52 (36.1)
< 0.001 < 0.001 0.302 < 0.001 0.015 0.490 0.010 0.026 0.129
0.085 267 (61.7) 166 (38.3)
93 (65) 50 (35)
70 (45.8) 51 (35.4)
80 (55.2) 65 (44.8) 0.209
239 (52.2) 220 (47.8) 184 (40.3)
90 (58.8) 63 (41.2) 71 (46.4)
70 (45.8) 83 (54.2) 49 (32)
79 (51.6) 74 (48.4) 64 (42.1)
0.414
IQR, interquartile range; NYHA, New York Heart Association functional classification; Nt-proBNP, N-terminal pro B-type natriuretic peptide.
Table 3 Univariable and multivariable Cox-regression analysis High-sensitivity C-reactive protein (continuous variable) .................................... HR per 1 SD P-value (95% CI)
Tertiles of high-sensitivity C-reactive protein
1.29 (1.12–1.49) 1.20 (1.02–1.40)
0.001 0.018
1 1
1.68 (1.14–2.47) 1.32 (0.88–1.98)
1.38 (1.15–2.40) < 0.001 1.32 (1.08–1.61) 0.005
1 1
1.91 (1.17–3.13) 0.01 1.54 (0.91–2.58) 0.105
...................................................................... 1 2 3 ........................... ............................ HR HR P-value HR (95% CI) Pnvalue (95% CI) (95% CI) ........................................................................................................................................... All-cause mortality Univariate Adjusted for baseline characteristics* Cardiovascular mortality Univariate Adjusted for baseline characteristics*
0.008 0.186
2.15 (1.47–3.12) < 0.001 1.83 (1.23–2.72) 0.002 2.41 (1.49–3.90) 2.21 (1.33–3.66)
< 0.001 0.002
power. In contrast, our study included an almost sixfold higher number of study participants, with a median follow-up time of almost 10 years. The concept of biomarker-supported care in HF, with Nt-proBNP already adopted in clinical practice, is attractive as it optimizes diagnostic algorithms, therapeutic decisions and risk stratification.18,19 While Nt-proBNP is an established marker
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CI, confidence interval; HR, Hazard ratio; SD, standard deviation. * Adjusted for age, sex, New York Heart Association functional classification, N-terminal pro B-type natriuretic peptide, estimated glomerular filtration rate, smoking, hypertension, coronary artery disease, diabetes, chronic obstructive pulmonary disease, atrial fibrillation, and heart rate.
for HF, CRP represents a sensitive and robust biomarker for assessment of a global cardiovascular risk, which is recommended by the ‘2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults’ as an additional risk marker in specific clinical situations associated with intermediate cardiovascular risk (class IIa, level of evidence B).9 Moreover, CRP has been successfully used in the Use of Statins in Prevention: an © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
CRP predicts mortality in patients referred for coronary angiography and HFpEF
(a)
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(b)
Figure 1 Survival curves according to high-sensitivity C-reactive protein tertiles. Kaplan–Meier plots show the crude cumulative survival
Intervention Trial Evaluating Rosuvastatin (JUPITER) to identify persons who may benefit from an intensified statin treatment in primary prevention.20 Our data extend the potential application of CRP as biomarker to patients with HFpEF. Using CRP as independent risk predictor may allow a more precise stratification of the heterogeneous risk of HFpEF patients. A CRP level above 7.33 mg/L will help to identify patients at very high risk, with a 5-year mortality rate of 27.5%. Moreover, CRP may optimize Nt-proBNP-guided risk prediction by adding predictive value (Figure 3). This may be of particular interest as recent data have shown that a Nt-proBNP-tailored therapy is less useful in HFpEF patients than in HFrEF patients.21,22 Heart failure constitutes a complex syndrome characterized by an underlying multisystemic interplay between structural, functional and biochemical aberrations of the myocardium including neurohumoral changes and activation of the immune system. In particular, the participation of immune cells and pro-inflammatory cytokines in the pathogenesis and progression of congestive heart failure (CHF) is well established.6 The use of biomarker reflecting immunological activation therefore seems attractive. Tumour necrosis factor alpha (TNF-𝛼), interleukin (IL)-1 and IL-6, closely linked with severity and outcome in CHF, are known to contribute to cardiac remodelling and left ventricular dysfunction by induction of hypertrophy, dilatation, fibrosis and apoptosis of cardiomyocytes.23 – 25 These inflammatory mediators act further as strong stimuli to release acute phase-reactants, mainly CRP, from activated hepatocytes.10 Although important mechanistic questions regarding the role of inflammation in CHF have not been answered up to now, activation of the immune system seems to follow different pathways in HFrEF and HFpEF. The source of proinflammatory cytokines in HFrEF may result from both a direct myocardial release in consequence of haemodynamic overload and
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free from all-cause mortality (a) and cardiovascular mortality (b) according to high-sensitivity C-reactive protein tertiles. Comparison between tertiles was assessed using log-rank test.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
as extramyocardial production caused by reduced tissue perfusion and associated hypoxia.26 In contrast, HFpEF develops as a consequence of a pre-existing inflammatory state predominantly driven by HF-related comorbidities such as CAD, type 2 diabetes mellitus, COPD, obesity, or hypertension with adverse effects on myocardial integrity.27 The inflammatory response promotes fibrotic remodelling of the myocardium by stimulating hypertrophy of cardiomyocytes and enhanced formation of collagen-producing myofibroblasts, both leading to increased stiffening and fibrosis of the heart. Based on this causal relationship with diastolic impairment in experimental studies inflammatory activation might become an attractive therapeutic target. The hypothesis of a comorbidity-triggered immune reaction leading to diastolic left ventricular dysfunction is well-grounded, as the aforementioned comorbidities are highly prevalent in HFpEF patients and are characterized by the ability to provoke a chronic and systemic immune response.27,28 Kalogeropoulos et al. found strong associations of baseline TNF-𝛼, IL-6 and CRP for the risk of incident HF during follow-up in a study of 2610 persons aged 70–79 years.29 Interestingly, these associations proved to be stronger for the development of HFpEF than HFrEF in this study cohort, supporting the hypothesis of adverse effects on myocardial integrity caused by inflammatory cytokines, particularly with respect to diastolic function. The current study extends the findings of Kalogeropoulos et al. as it shows that the association between CRP and HFpEF may be explained by an increase of CRP in HFpEF patients because of comorbidities such as CAD, COPD, type II diabetes mellitus and high BMI. Exact interactions and mechanistic processes between non-cardiac comorbidities and myocardial deterioration in HFpEF are certainly complex and may vary depending on individual risk profiles. Nevertheless (or rather because), a marker reflecting a relatively unspecific inflammatory
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process may be a valuable clinical tool for risk stratification in these patients with multiple and heterogeneous comorbidities that have inflammatory activation as common denominator. In the present study, CRP showed a particularly strong predictive value for cardiovascular mortality, which is the more disease-specific endpoint. This finding is not surprising as the role of CRP in the development and progression of atherosclerosis, the underlying pathophysiological background of CAD and myocardial infarction, has been widely examined. Elevated CRP levels indicate development, progression and destabilization of atherosclerotic lesions. Briefly, CRP induces expression of adhesion molecules on vascular endothelial cells thereby facilitating adhesion and transmigration of monocytes, differentiation into proatherogenic M1 macrophages and is suspected to promote impairment of vasoreactivity by inhibition of endothelial nitric oxide synthase.30,31 However, whether CRP is directly involved in the atherosclerotic process or is a relatively unspecific surrogate marker of concomitant immune activation is unclear.32,33 A greater prognostic value of CRP in the subgroup without CAD in this study may support an immune-mediated impairment of cardiac function in HFpEF rather than a direct atherosclerotic effect, although future mechanistic
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Figure 2 Hazard ratio plot (Forest plot) of high-sensitivity C-reactive protein according to major subgroups. NYHA, New York Heart Association functional classification; BMI, body mass index; Nt-proBNP, N-terminal pro B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease.
studies are necessary to distinguish between the underlying pathways. A limitation of the study is that a specific echocardiographic analysis of diastolic function was not routinely performed at time of study enrolment. However, for the majority of study patients invasive haemodynamic measurements were available for the identification of HFpEF, as currently recommended as appropriate diagnostic tool by the Heart Failure and Echocardiography Associations of the European Society of Cardiology.15 In addition, HFpEF patients were identified in the LURIC study, which included patients referred for coronary angiography. This source population may have biased the selection of patients compared with a community-based HFpEF cohort. The HFpEF patients not referred to coronary angiography were therefore not included in this study population. As a further limitation, patients with HFpEF have been retrospectively identified according to current guidelines in the prospectively collected LURIC database. Moreover, it should be mentioned that adjustment for potential confounders in the multivariable model is based on known risk factors for progression of HFpEF and may not include other currently unknown confounders. © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
CRP predicts mortality in patients referred for coronary angiography and HFpEF
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(b)
In conclusion, CRP proved be a strong prognostic marker for risk stratification in patients with HFpEF. The high number of study participants and a follow-up of 10 years corresponding to 3862 person-years of follow-up results in ample statistical power of this analysis. The predictive value of CRP was independent of traditional HF-related risk factors and was particularly strong for cardiovascular mortality. Simultaneous assessment of CRP and Nt-proBNP, both representing different pathophysiological pathways in HFpEF, may offer an even better risk prediction. A combination of these established cardiovascular biomarkers may help to identify individuals with an increased risk for future cardiovascular events. Finally, our study supports the notion of an underlying inflammatory process in the complex and multifactorial pathophysiology of HFpEF.
Acknowledgements The authors thank the patients of the LURIC study for their participation in data collection and assessment. They also thank the LURIC study team either temporarily or permanently involved in patient recruitment and sample and data handling, the laboratory staff at the Ludwigshafen General Hospital, and the Universities of Freiburg, Ulm, Graz, and Heidelberg. The authors thank the German registration offices and local public health departments for their assistance.
Supplementary Information Additional Supporting Information may be found in the online version of this article:
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Figure 3 Risk in combined strata according to high-sensitivity C-reactive protein and N-terminal pro B-type natriuretic peptide tertiles. The figure shows relative risk stratified by combined tertiles of high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide for all-cause mortality (a) and cardiovascular mortality (b).
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Table S1. Baseline characteristics of patients with heart failure with reduced ejection fraction
Funding G.G. was funded by an Erwin Schrödinger Fellowship of the Austrian Science Fund (FWF J 3319-B13). LURIC has received funding through the 6th Framework Programme (integrated project Bloodomics, grant LSHMCT-2004–503485), from the 7th Framework Programme (integrated projects Atheroremo, Grant Agreement Number 201668 and RiskyCAD, grant agreement number 305739) of the European Union and from the INTERREG IV Oberrhein Programme (Project A28, Genetic Mechanisms of Cardiovascular Diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO. Roche Diagnostics (Mannheim, Germany) provided reagents for the determination of Nt-proBNP free of charge. None of the sponsors had an involvement in the design and conducting of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript. Conflict of interest: none declared.
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© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction L. Koller1†, M. Kleber2†, G. Goliasch1,3, P. Sulzgruber1, H. Scharnagl4, G. Silbernagel5, T. Grammer2,6, G. Delgado2, A. Tomaschitz7,8, S. Pilz9, W. März2,4,10, and A. Niessner1* 1 Division
of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Austria; 2 Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; 3 Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA; 4 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; 5 Department of Angiology, Inselspital, Bern, Switzerland; 6 Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Germany; 7 Sonderkrankenanstalt Rehabilitationszentrum Bad Aussee, Bad Aussee, Austria; 8 Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria; 9 Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria; and 10 Synlab Academy, Synlab Services GmbH, Mannheim, Germany Received 14 January 2014; revised 14 March 2014; accepted 21 March 2014 ; online publish-ahead-of-print 7 May 2014
Aims
Heart failure with preserved ejection fraction (HFpEF) has a different pathophysiological background compared to heart failure with reduced ejection fraction (HFrEF). Tailored risk prediction in this separate heart failure group with a high mortality rate is of major importance. Inflammation may play an important role in the pathogenesis of HFpEF because of its significant contribution to myocardial fibrosis. We therefore aimed to assess the predictive value of C-reactive protein (CRP) in patients with HFpEF. ..................................................................................................................................................................... Methods Plasma levels of CRP were determined in 459 patients with HFpEF in the LUdwigshafen Risk and Cardiovascular and results Health (LURIC) study using a high-sensitivity assay. During a median follow-up of 9.7 years 40% of these patients died. CRP predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.20 [95% confidence interval (CI) 1.02–1.40, P = 0.018] and cardiovascular mortality with a HR of 1.32 (95% CI 1.08–1.62, P = 0.005) per increase of one standard deviation. CRP was a significantly stronger mortality predictor in HFpEF patients than in a control group of 522 HFrEF patients (for interaction, P = 0.015). Furthermore, CRP added prognostic value to N-terminal pro B-type natriuretic peptide (Nt-proBNP): the lowest 5-year mortality rate of 6.8% was observed for patients in the lowest tertile of Nt-proBNP as well as CRP. The mortality risk peaked in the group combining the highest values of Nt-proBNP and CRP with a 5-year rate of 36.5%. ..................................................................................................................................................................... Conclusion It was found that CRP was an independent and strong predictor of mortality in HFpEF. This observation may reflect immunological processes with an adverse impact on the course of HFpEF.
.......................................................................................................... Keywords
Biomarker • Inflammation
Heart failure with preserved ejection fraction •
High-sensitivity C-reactive protein •
*Corresponding author. Tel: +43 1404004614, Fax: +43 1404004216, Email: [email protected] † These authors contributed equally to this work.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Introduction During the last decades heart failure (HF) with preserved ejection fraction (HFpEF) was identified as a distinct entity of HF with different pathophysiology and patient characteristics compared with HF with reduced ejection fraction (HFrEF).1 – 3 Therefore, targeted risk prediction is of utmost importance in this group of patients with relatively high risk of fatal and non-fatal cardiovascular events.4 Activation of the immune system has been shown to be crucially implicated in chronic HF.5 More precisely, high plasma concentrations of several pro-inflammatory cytokines are closely linked with disease progression and poor prognosis.6 However, most studies addressing immunological processes in HF have been performed in patients with HFrEF, while evidence about inflammatory processes in the pathophysiology of HFpEF is relatively scarce.7,8 It has been determined that C-reactive protein (CRP) is one of the most promising markers for risk assessment in clinical practice and is therefore recommended for risk stratification in the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guidelines for Assessment of Cardiovascular Risk in Asymptomatic Adults.9 CRP, an acute-phase reactant predominantly released from hepatocytes, is a non-specific inflammatory marker clearly associated with adverse cardiovascular disease (CVD) outcomes.10 While CRP has been examined in large epidemiological studies, and in a variety of clinical settings including patients with HFrEF, only scarce data are available in patients with HFpEF.11 – 13 Based on the pathophysiological role of inflammation in cardiovascular diseases and its association with fibrosis we hypothesized that CRP may be a useful marker for refining risk prediction in HFpEF patients with underlying myocardial fibrosis. Therefore, we assessed the predictive power of CRP in a prospective registry including 459 patients presenting with HFpEF. In addition to the impact of CRP on mortality, we specifically focused on the gain in risk prediction beyond N-terminal pro B-type natriuretic peptide (Nt-proBNP), which is currently the most important biomarker in HF risk assessment.
Methods Study population Patients included in this analysis were participants of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. The detailed study protocol has been described previously.14 In brief, 3316 patients referred to the Heart Centre of Ludwigshafen for coronary angiography were enrolled between July 1997 and January 2000. To address the study goals, we identified 506 patients with HFpEF in a stable condition according to current recommendations of the Heart Failure and Echocardiography Associations of the European Society of Cardiology.15 After exclusion of acute or chronic infection, autoimmune diseases and cancer, the final patient cohort comprised 459 patients. All patients with the following characteristics were included: symptoms and signs of HF, a preserved left ventricular function with an ejection fraction >45% (echocardiographic or invasive) and the presence of diastolic HF according to the definition published by Paulus et al.15 In particular, diastolic dysfunction was diagnosed in 388 patients (85%) based on haemodynamic criteria (mean pulmonary
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CRP predicts mortality in patients referred for coronary angiography and HFpEF
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
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capillary wedge pressure >12 mmHg or a left ventricular end-diastolic pressure >16 mmHg). In the remaining 71 patients (15%) diastolic dysfunction was identified by an elevated Nt-proBNP concentration (>220 pg/mL) and electrocardiographic evidence of atrial fibrillation. Written informed consent was obtained from all study participants. The LURIC study complies with the Declaration of Helsinki and was approved by the Ethics Committee of the ‘Landesärztekammer Rheinland-Pfalz’ (Mainz, Germany).
Follow-up and study endpoints All-cause and cardiovascular mortality were chosen as primary study endpoints and were obtained by browsing local community registries, including revision of death certificates to classify these into cardiovascular and non-cardiovascular causes of death, as previously described.16 Cardiovascular mortality included fatal myocardial infarction, sudden cardiac death, death after cardiovascular intervention, stroke and other causes of death resulting from cardiac diseases. A sample size of 460 patients with 40% of patients experiencing the primary endpoint enabled detection of a risk ratio of 1.5 between 1st and 3rd tertile (𝛼 = 0.05, power = 80%).
Blood sampling and laboratory analyses Venous blood samples were taken at study enrolment in the supine position. Routine laboratory parameters were analysed according to local laboratory standard procedures. For the measurement of further biomarkers ethylenediaminetetraacetic acid (EDTA) plasma samples were snap frozen at −80∘ C after centrifugation (1825 g, 20 min) and stored until analysis. The CRP concentrations were measured using high-sensitivity immunonephelometry (Dade Behring, Marburg, Germany). Interassay and intra-assay CVs were 55%, n (%) 45–55%, n (%) Left ventricular end-diastolic pressure ≤16 mmHg, n (%) >16 mmHg, n (%) Pulmonary wedge capillary pressure ≤12 mmHg, n (%) >12 mmHg, n (%) Atrial fibrillation, n (%)
3.88 (1.36–9.37)
1.00 (0.69–1.37)
3.88 (2.59–5.42)
13.8 (9.3–3.35)
99 (21.5) 13 (2.8)
16 (10.5) 2 (1.3)
37 (24.2) 6 (3.9)
46 (30.1) 5 (3.3)
64 (14.4) 241 (54.0) 141 (31.6) 533 (245–1306)
29 (19.1) 85 (55.9) 37 (24.3) 434 (179–857)
21 (14.7) 73 (51.0) 49 (34.4) 534 (246–1583)
12 (8.2) 81 (55.1) 54 (36.7) 748 (300–1662)
310 (70.3) 131 (29.7)
110 (74.3) 38 (25.7)
107 (72.3) 41 (27.7)
92 (63.9) 52 (36.1)
< 0.001 < 0.001 0.302 < 0.001 0.015 0.490 0.010 0.026 0.129
0.085 267 (61.7) 166 (38.3)
93 (65) 50 (35)
70 (45.8) 51 (35.4)
80 (55.2) 65 (44.8) 0.209
239 (52.2) 220 (47.8) 184 (40.3)
90 (58.8) 63 (41.2) 71 (46.4)
70 (45.8) 83 (54.2) 49 (32)
79 (51.6) 74 (48.4) 64 (42.1)
0.414
IQR, interquartile range; NYHA, New York Heart Association functional classification; Nt-proBNP, N-terminal pro B-type natriuretic peptide.
Table 3 Univariable and multivariable Cox-regression analysis High-sensitivity C-reactive protein (continuous variable) .................................... HR per 1 SD P-value (95% CI)
Tertiles of high-sensitivity C-reactive protein
1.29 (1.12–1.49) 1.20 (1.02–1.40)
0.001 0.018
1 1
1.68 (1.14–2.47) 1.32 (0.88–1.98)
1.38 (1.15–2.40) < 0.001 1.32 (1.08–1.61) 0.005
1 1
1.91 (1.17–3.13) 0.01 1.54 (0.91–2.58) 0.105
...................................................................... 1 2 3 ........................... ............................ HR HR P-value HR (95% CI) Pnvalue (95% CI) (95% CI) ........................................................................................................................................... All-cause mortality Univariate Adjusted for baseline characteristics* Cardiovascular mortality Univariate Adjusted for baseline characteristics*
0.008 0.186
2.15 (1.47–3.12) < 0.001 1.83 (1.23–2.72) 0.002 2.41 (1.49–3.90) 2.21 (1.33–3.66)
< 0.001 0.002
power. In contrast, our study included an almost sixfold higher number of study participants, with a median follow-up time of almost 10 years. The concept of biomarker-supported care in HF, with Nt-proBNP already adopted in clinical practice, is attractive as it optimizes diagnostic algorithms, therapeutic decisions and risk stratification.18,19 While Nt-proBNP is an established marker
...................
CI, confidence interval; HR, Hazard ratio; SD, standard deviation. * Adjusted for age, sex, New York Heart Association functional classification, N-terminal pro B-type natriuretic peptide, estimated glomerular filtration rate, smoking, hypertension, coronary artery disease, diabetes, chronic obstructive pulmonary disease, atrial fibrillation, and heart rate.
for HF, CRP represents a sensitive and robust biomarker for assessment of a global cardiovascular risk, which is recommended by the ‘2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults’ as an additional risk marker in specific clinical situations associated with intermediate cardiovascular risk (class IIa, level of evidence B).9 Moreover, CRP has been successfully used in the Use of Statins in Prevention: an © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
CRP predicts mortality in patients referred for coronary angiography and HFpEF
(a)
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(b)
Figure 1 Survival curves according to high-sensitivity C-reactive protein tertiles. Kaplan–Meier plots show the crude cumulative survival
Intervention Trial Evaluating Rosuvastatin (JUPITER) to identify persons who may benefit from an intensified statin treatment in primary prevention.20 Our data extend the potential application of CRP as biomarker to patients with HFpEF. Using CRP as independent risk predictor may allow a more precise stratification of the heterogeneous risk of HFpEF patients. A CRP level above 7.33 mg/L will help to identify patients at very high risk, with a 5-year mortality rate of 27.5%. Moreover, CRP may optimize Nt-proBNP-guided risk prediction by adding predictive value (Figure 3). This may be of particular interest as recent data have shown that a Nt-proBNP-tailored therapy is less useful in HFpEF patients than in HFrEF patients.21,22 Heart failure constitutes a complex syndrome characterized by an underlying multisystemic interplay between structural, functional and biochemical aberrations of the myocardium including neurohumoral changes and activation of the immune system. In particular, the participation of immune cells and pro-inflammatory cytokines in the pathogenesis and progression of congestive heart failure (CHF) is well established.6 The use of biomarker reflecting immunological activation therefore seems attractive. Tumour necrosis factor alpha (TNF-𝛼), interleukin (IL)-1 and IL-6, closely linked with severity and outcome in CHF, are known to contribute to cardiac remodelling and left ventricular dysfunction by induction of hypertrophy, dilatation, fibrosis and apoptosis of cardiomyocytes.23 – 25 These inflammatory mediators act further as strong stimuli to release acute phase-reactants, mainly CRP, from activated hepatocytes.10 Although important mechanistic questions regarding the role of inflammation in CHF have not been answered up to now, activation of the immune system seems to follow different pathways in HFrEF and HFpEF. The source of proinflammatory cytokines in HFrEF may result from both a direct myocardial release in consequence of haemodynamic overload and
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free from all-cause mortality (a) and cardiovascular mortality (b) according to high-sensitivity C-reactive protein tertiles. Comparison between tertiles was assessed using log-rank test.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
as extramyocardial production caused by reduced tissue perfusion and associated hypoxia.26 In contrast, HFpEF develops as a consequence of a pre-existing inflammatory state predominantly driven by HF-related comorbidities such as CAD, type 2 diabetes mellitus, COPD, obesity, or hypertension with adverse effects on myocardial integrity.27 The inflammatory response promotes fibrotic remodelling of the myocardium by stimulating hypertrophy of cardiomyocytes and enhanced formation of collagen-producing myofibroblasts, both leading to increased stiffening and fibrosis of the heart. Based on this causal relationship with diastolic impairment in experimental studies inflammatory activation might become an attractive therapeutic target. The hypothesis of a comorbidity-triggered immune reaction leading to diastolic left ventricular dysfunction is well-grounded, as the aforementioned comorbidities are highly prevalent in HFpEF patients and are characterized by the ability to provoke a chronic and systemic immune response.27,28 Kalogeropoulos et al. found strong associations of baseline TNF-𝛼, IL-6 and CRP for the risk of incident HF during follow-up in a study of 2610 persons aged 70–79 years.29 Interestingly, these associations proved to be stronger for the development of HFpEF than HFrEF in this study cohort, supporting the hypothesis of adverse effects on myocardial integrity caused by inflammatory cytokines, particularly with respect to diastolic function. The current study extends the findings of Kalogeropoulos et al. as it shows that the association between CRP and HFpEF may be explained by an increase of CRP in HFpEF patients because of comorbidities such as CAD, COPD, type II diabetes mellitus and high BMI. Exact interactions and mechanistic processes between non-cardiac comorbidities and myocardial deterioration in HFpEF are certainly complex and may vary depending on individual risk profiles. Nevertheless (or rather because), a marker reflecting a relatively unspecific inflammatory
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process may be a valuable clinical tool for risk stratification in these patients with multiple and heterogeneous comorbidities that have inflammatory activation as common denominator. In the present study, CRP showed a particularly strong predictive value for cardiovascular mortality, which is the more disease-specific endpoint. This finding is not surprising as the role of CRP in the development and progression of atherosclerosis, the underlying pathophysiological background of CAD and myocardial infarction, has been widely examined. Elevated CRP levels indicate development, progression and destabilization of atherosclerotic lesions. Briefly, CRP induces expression of adhesion molecules on vascular endothelial cells thereby facilitating adhesion and transmigration of monocytes, differentiation into proatherogenic M1 macrophages and is suspected to promote impairment of vasoreactivity by inhibition of endothelial nitric oxide synthase.30,31 However, whether CRP is directly involved in the atherosclerotic process or is a relatively unspecific surrogate marker of concomitant immune activation is unclear.32,33 A greater prognostic value of CRP in the subgroup without CAD in this study may support an immune-mediated impairment of cardiac function in HFpEF rather than a direct atherosclerotic effect, although future mechanistic
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Figure 2 Hazard ratio plot (Forest plot) of high-sensitivity C-reactive protein according to major subgroups. NYHA, New York Heart Association functional classification; BMI, body mass index; Nt-proBNP, N-terminal pro B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease.
studies are necessary to distinguish between the underlying pathways. A limitation of the study is that a specific echocardiographic analysis of diastolic function was not routinely performed at time of study enrolment. However, for the majority of study patients invasive haemodynamic measurements were available for the identification of HFpEF, as currently recommended as appropriate diagnostic tool by the Heart Failure and Echocardiography Associations of the European Society of Cardiology.15 In addition, HFpEF patients were identified in the LURIC study, which included patients referred for coronary angiography. This source population may have biased the selection of patients compared with a community-based HFpEF cohort. The HFpEF patients not referred to coronary angiography were therefore not included in this study population. As a further limitation, patients with HFpEF have been retrospectively identified according to current guidelines in the prospectively collected LURIC database. Moreover, it should be mentioned that adjustment for potential confounders in the multivariable model is based on known risk factors for progression of HFpEF and may not include other currently unknown confounders. © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
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(b)
In conclusion, CRP proved be a strong prognostic marker for risk stratification in patients with HFpEF. The high number of study participants and a follow-up of 10 years corresponding to 3862 person-years of follow-up results in ample statistical power of this analysis. The predictive value of CRP was independent of traditional HF-related risk factors and was particularly strong for cardiovascular mortality. Simultaneous assessment of CRP and Nt-proBNP, both representing different pathophysiological pathways in HFpEF, may offer an even better risk prediction. A combination of these established cardiovascular biomarkers may help to identify individuals with an increased risk for future cardiovascular events. Finally, our study supports the notion of an underlying inflammatory process in the complex and multifactorial pathophysiology of HFpEF.
Acknowledgements The authors thank the patients of the LURIC study for their participation in data collection and assessment. They also thank the LURIC study team either temporarily or permanently involved in patient recruitment and sample and data handling, the laboratory staff at the Ludwigshafen General Hospital, and the Universities of Freiburg, Ulm, Graz, and Heidelberg. The authors thank the German registration offices and local public health departments for their assistance.
Supplementary Information Additional Supporting Information may be found in the online version of this article:
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Figure 3 Risk in combined strata according to high-sensitivity C-reactive protein and N-terminal pro B-type natriuretic peptide tertiles. The figure shows relative risk stratified by combined tertiles of high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide for all-cause mortality (a) and cardiovascular mortality (b).
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Table S1. Baseline characteristics of patients with heart failure with reduced ejection fraction
Funding G.G. was funded by an Erwin Schrödinger Fellowship of the Austrian Science Fund (FWF J 3319-B13). LURIC has received funding through the 6th Framework Programme (integrated project Bloodomics, grant LSHMCT-2004–503485), from the 7th Framework Programme (integrated projects Atheroremo, Grant Agreement Number 201668 and RiskyCAD, grant agreement number 305739) of the European Union and from the INTERREG IV Oberrhein Programme (Project A28, Genetic Mechanisms of Cardiovascular Diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO. Roche Diagnostics (Mannheim, Germany) provided reagents for the determination of Nt-proBNP free of charge. None of the sponsors had an involvement in the design and conducting of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript. Conflict of interest: none declared.
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© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
