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Propeptide of procollagen type I (PIP) and outcomes in decompensated heart failure
European Journal of Internal Medicine 18 (2007) 129 – 134 www.elsevier.com/locate/ejim
Original article
Propeptide of procollagen type I (PIP) and outcomes in decompensated heart failure ☆ Francisco J. Ruiz-Ruiz a , Fernando José Ruiz-Laiglesia a , Pilar Samperiz-Legarre a , Pilar Lasierra-Diaz b , Álvaro Flamarique-Pascual a , José L. Morales-Rull a , Juan I. Perez-Calvo a,⁎ a
Internal Medicine Department, Hospital Clínico Universitario “Lozano Blesa”, Avenida San Juan Bosco, 15, Zaragoza 50009, Spain b Immunology Department, Hospital Clínico Universitario “Lozano Blesa”, Avenida San Juan Bosco, 15, Zaragoza 50009, Spain Received 6 April 2006; received in revised form 25 July 2006; accepted 19 September 2006
Abstract Background: Changes in extracellular matrix are recognized as a contributing factor in the cardiac remodeling process. Several studies have addressed the value of turnover markers of collagen as predictors of death or new heart failure episodes. The aim of the present study was to evaluate the relationship between peripheral serum concentration of propeptide of procollagen type I (PIP) and outcomes in patients with decompensated heart failure. Methods: A total of 111 patients admitted to our Unit between September 2000 and May 2003 for decompensated heart failure were analyzed. Death from any cause or due to heart failure and readmission were considered primary endpoints. Results: The mean PIP concentration was 80.84 ± 36.40 ng/mL. The PIP serum level was significantly higher among those patients who suffered some endpoint during follow-up (88.12 ± 37.31 ng/mL vs 73.13 ± 34.06 ng/mL; p = 0.029). Twenty-five (22.52%) of the 111 patients died during the 21 months of follow-up, and 54 (48.6%) were readmitted with new bouts of heart failure. Using Cox proportional hazards regression analyses, serum PIP levels, systolic dysfunction, and diabetes mellitus were identified as independent predictors of death. Serum PIP levels, age, and sex were independent predictors of new heart failure episodes and readmission. Conclusion: A single serum measurement of PIP seems to have prognostic value in patients with decompensated heart failure. Accordingly, patients with higher values of PIP at decompensation are at a higher risk of death or readmission during follow-up. © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Propeptide of procollagen type I (PIP); Decompensated heart failure; Prognosis
1. Introduction Changes in extracellular matrix, elicited by essential hypertension or myocardial infarction, are recognized as a contributing factor in the cardiac remodeling process.
☆
Data from the manuscript have been presented at the XXVI Congreso Nacional de la Sociedad Española de Medicina Interna. ⁎ Corresponding author. Servicio de Medicina Interna, Hospital Clínico Universitario “Lozano Blesa”, Avenida San Juan Bosco, 15, Zaragoza 50009, Spain. Tel.: +34 976 556 400x2604; fax: +34 976 351 661. E-mail address: [email protected] (J.I. Perez-Calvo).
Myocardial fibrosis contributes to systolic and diastolic ventricular dysfunction and provides the structural substrate for arrythmogenicity, thus potentially contributing to sudden death. Cardiac remodeling is defined by structural changes at the cardiac myocyte level that are translated into alterations in chamber size and geometry. Pressure and volume overload lead to changes in myocardial gene expression of contractile proteins and calcium handling that interfere with contractile function [1–4]. Collagen provides architectural support for the muscle cells and plays an important role in myocardial function. Molecules of synthesis and degradation of collagen (type I and type III collagen) have been used to monitor the fibrosis
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process [5]. Types I and III are the two major types of collagen present in the myocardium in both normal and diseased myocardial tissue. Normal adult myocardium is governed by a balanced equilibrium between stimulator and inhibitor signals (such as prostaglandins, endothelin, bradykinin, angiotensin, transforming growth factor, nitric oxide, or aldosterone) that regulate cell growth, apoptosis, and collagen turnover. In heart failure, a complex series of molecular events that include the expression of genes and activation of multiple second messenger system alter the composition of the extracellular matrix. The prognosis of heart failure is bleak and may be worse than that for most types of cancer [6,7]. Several studies have addressed the value of turnover markers of collagen as predictors of death or new heart failure episodes. Procollagen type III aminoterminal peptide (PIIINP) has been found to be increased in patients with hypertensive left ventricular hypertrophy, ventricular dysfunction after acute myocardial infarction, or dilated cardiomyopathy [8,9]. Indeed, high serum levels of PIIINP are significantly associated with poor outcome [10–13]. The carboxyterminal propeptide of type I procollagen (PIP), a molecule of collagen synthesis, seems useful in predicting the development of heart failure among patients with acute myocardial infarction or hypertension and might be a valuable marker for progression of left ventricular dilation [14–16]. The aim of the present study was to evaluate the relationship between peripheral serum concentration of PIP and outcomes in elderly patients with decompensated heart failure. 2. Methods 2.1. Patients, study design, procedures, and endpoints One hundred and eleven patients were admitted to our Unit between September 2000 and May 2003 because of decompensated heart failure. Patients with diseases that can modify prognosis, such as neoplasm, severe infection, and Alzheimer's or neurodegenerative disease, were excluded. Patients with alcoholic liver disease, renal insufficiency (creatinine clearance b 20 mL/ min, estimated by Gault–Cockroft equation), hyperthyroidism, or metabolic bone disease were excluded because these diseases can modify the serum concentration of PIP. Patients older than 85 years were also excluded from the study to avoid possible biases on endpoints. Finally, patients who died during the initial (index) hospitalization were also excluded from the analysis. The diagnosis of heart failure was made on the basis of clinical and echocardiographic findings, according to the Framingham and Boston criteria [17]. Acute left heart decompensation was based on an increase in dyspnea or orthopnea, pulmonary rales, or radiographic findings consistent with pulmonary edema. Death from any cause or due to heart failure and readmission were considered primary endpoints.
Blood samples were taken during the first 72 h after clinical admission. Each sample was centrifuged at 3000 rpm for 10 min at 4 °C, separated, and stored at −40 °C until analysis. Serum PIP was determined by ELISA (Procollagen type I Cpeptide EIA kit; precoated; Takara Bio, Inc). The PIP EIA kit is a solid-phase enzyme immunoassay based on a sandwich method that utilizes two mouse monoclonal anti-PIP antibodies to detect PIP by a one-step procedure. The inter-assay and intra-assay variations for determining PIP were 6.3% and 7.4%, respectively. The sensitivity was 10 ng/mL. We selected 25 patients admitted for causes not related to heart disease as a control group. Mean PIP values for controls were 54.03 ± 14.89 ng/mL (range 42.19 to 89.73 ng/mL). Echocardiography was performed during admission on each patient unless it had been performed less than 3 months earlier. According to left ventricular ejection fraction (LVEF) measurement, patients were classified into two groups: those with systolic dysfunction (LVEF b 40%) and those with preserved LVEF (N 40%), according to the Vasan and Levy criteria [18]. Informed consent for the test, stored samples, and review of the records was obtained from all participants. 2.2. Statistical analysis Values are expressed as mean ± SD or percentage, depending on the type of variable. The Statistical Program for the Social Science (SPSS) was used for data entry and processing. Student's t-test was used to test for differences in continuous variables and the χ2 test was used for categorical variables. Receiver-operating-characteristic (ROC) analysis was performed for PIP levels. Long-term survival was assessed from the day of admission to the hospital to the day of death or to 1 March 2004. Cumulative survival curves were constructed according to the Kaplan–Maier method, and differences between curves were tested with the log-rank test. Predictors of new heart failure episodes or death were analyzed by Cox proportional hazards analysis. p values less than 0.05 were considered statistically significant. 3. Results Demographic characteristics of the patients are shown in Table 1. Analyzing the age variable, 12.6% of the patients were younger than 65 and 50% were between 75 and 85 years old. Fifty-five patients (49.5%) had a previous diagnosis of heart failure; 43 of them had been admitted earlier for this reason. Factors triggering decompensation could not be elucidated in 51 patients (45.9%). In such cases, mild viral infection and lack of diet or drug adherence were considered the most probable causes. The mean PIP concentration was 80.84 ± 36.40 ng/mL (range 33.94 to 244.88 ng/mL). There were no differences in PIP concentration with regard to age, sex or cause of heart
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Table 1 Clinical characteristics of the population Clinical characteristics
Value
Age (years) Male Prior heart failure Hypertensive etiology Ischemic etiology Other etiologies Systolic dysfunction Heart failure with ejection fraction preserved
73.45 ± 7.95 59 (53.2%) 55 (49.5%) 32 (28.8%) 40 (36.0%) 28 (35.2%) 51 (45.9%) 60 (54.1%)
Echocardiographic parameters Ejection fraction (%) End-systolic diameter of left ventricle (mm) End-diastolic diameter of left ventricle (mm) Previous treatment with ACE inhibitors or ARB
49.7 ± 15.3 37.4 ± 10.9 53.9 ± 9.6 51 (45.9%)
Associated diseases Diabetes Hypertension Chronic obstructive pulmonary disease
34 (30.6%) 60 (54.1%) 25 (22.5%)
NYHA: New York Heart Association. ACE: angiotensin-converting enzyme. ARB: angiotensin receptor blockers.
failure. There was no correlation between serum PIP levels and LVEF. All patients admitted were in class III or IVof the New York Heart Association (NYHA). For analytical purposes, we considered basal functional class, according to the NYHA. Consequently, patients in basal class III or IVof the NYHA had higher concentrations than those in basal class I or II of the NYHA (97.26 ± 46.48 ng/mL vs 77.46 ± 38.70 ng/mL), but the difference was not statistically significant (p = 0.082). Among the 54 patients with some primary endpoints at follow-up (new hospitalizations or death), PIP levels were higher than in the 57 patients without them (88.12 ± 37.31 ng/ mL vs 73.13 ± 34.06 ng/mL; p = 0.029). Twenty-five of the 111 patients (22.52%) died during the 21 months of follow-up. In 22 (19.82%), the cause of death was related to heart failure. Three additional patients died of non-related causes and 86 remained alive.
Fig. 2. Curves showing patients who were readmitted due to new heart failure episodes. The broken line shows patients with serum PIP levels above 124 ng/mL.
Fifty-four patients (48.6%) were readmitted to the hospital with new bouts of heart failure. Some 26 patients were readmitted once, 15 patients twice, 7 patients three times, and 6 patients more than three times. A weak correlation between serum PIP levels and number of new episodes of heart failure was found (r = 0.26, p = 0.006). During follow-up, patients with a lower serum PIP concentration fared significantly better than those with a higher serum PIP concentration (mean survival 1090 vs 449 days). A PIP level above 124 ng/mL was predictive of death (log-rank test, p b 0.001) and new heart failure episodes (log-rank test, p b 0.003), according to the Kaplan–Maier survival method (Figs. 1 and 2). There were no differences in mortality and/or new episodes of heart failure according to etiology or comorbidity (including diabetic and non-diabetic patients). Using Cox proportional hazards regression analyses (Table 2), serum PIP levels, systolic dysfunction, and diabetes mellitus were identified as independent predictors of death. Serum PIP levels, age, and sex were independent predictors of new heart failure episodes and readmission.
Table 2 Predictors of death or the need for readmission due to heart failure during follow-up (multivariate analysis)
Fig. 1. Mortality curves illustrating deaths due to heart failure. The broken line shows patients with serum PIP levels above 124 ng/mL.
Variable
Readmission due to heart failure
Death due to heart failure
OR
OR
Age Sex (male) Diabetes mellitus Systolic dysfunction Serum PIP levels
1.059 1.006–1.115 0.028 1.002 0.920–1.092 0.960 2.079 1.078–4.000 0.029 1.960 0.618–6.211 0.252 1.416 0.874–2.881 0.336 6.535 1.773–23.80 0.005
95% CI
p
95% CI
p
1.540 0.793–2.994 0.202 3.623 1.079–12.19 0.037 1.015 1.006–1.024 0.001 1.036 1.017–1.055 0.001
OR: odds ratio. CI: confidence intervals.
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The area under the ROC for readmissions due to new heart failure episodes was 0.647 (95% CI 0.545–0.75) and it was 0.659 (95% CI 0.527–0.791) for death due to heart failure. ROC curves for various PIP cut-off values were calculated. A cut-off value of 124 ng/mL predicted prognosis most accurately. 4. Discussion Heart failure is a major health problem in developed countries and accounts for a large proportion of hospital admissions and deaths. Early diagnosis and correct therapy are key factors to reducing morbidity and mortality in such patients. Certain biochemical markers and neurohormones have prognostic value for patients with heart failure. Creactive protein (CRP), interleukin-6 (IL-6), and erythrocyte sedimentation rate (ESR) have been studied in heart failure, but with different results [19–21]. B-type natriuretic peptides (BNP and NT-proBNP) serve for risk stratification in large groups of patients suffering from heart failure [22,23]. Strategies based on BNP-guided therapy have been shown to be more efficient than those relying exclusively on clinical findings among patients with heart failure [24]. Accordingly, identification of biochemical markers, and especially their correlation with clinical outcomes, can help to identify groups of patients at a higher risk of complications or those who need a stricter follow-up and/or an intensified drug therapy. Several studies have addressed the role of molecule degradation of collagen type I (ICTP) in heart failure. Klappacher et al. showed that levels of PIIINP and ICTP were independent predictors of mortality [10]. Patients with higher circulating levels of extracellular matrix proteins were those at an increased relative risk of advanced clinical stage hyponatremia, poor hemodynamic condition, heart transplantation, and death during followup, as compared to patients with lower circulating levels. Collagen type I is characterized by strength and stiffness, whereas collagen type III is characterized by elasticity. Pauschinger et al. reported an increase in the collagen type I/III ratio in patients with dilated cardiomyopathy, something that would reflect an increasing myocardial stiffness, compromising diastolic and systolic function of the myocardium [25]. In our series, PIP was measured in 111 patients admitted for acutely decompensated chronic heart failure. The group, as a whole, is representative of the spectrum of patients admitted in current clinical practice. In our study, serum PIP levels showed a significant correlation with clinical outcome at 21 months. A PIP cut-off value of 124 pg/mL identified those patients who had a greater probability of death and new admissions at follow-up. Decompensated heart failure has been associated with increased mRNA expression of matrix proteins (types I and III collagen) and encoded proteins [26]. The results of our study are in keeping with these findings and support the
notion that the increase in serum markers of collagen synthesis might correlate with clinical outcome. Myocardial fibrosis is the consequence of either increased collagen synthesis or decreased extracellular matrix degradation. It has been involved in left ventricular dysfunction in patients with both systolic and diastolic dysfunction. Hemodynamic and non-hemodynamic factors have been involved in such an imbalance. Neurohormones, cytokines, and drugs play a role in myocardial fibrosis [1]. A close relationship between angiotensin II (AgII) and profibrotic cytokines represented by peptides belonging to the transforming growth factor beta (TGF-β) family has been suggested. Accordingly, binding of TGF-β 1 to their receptors on fibroblasts regulates the expression of type I collagen and favors fibrous tissue formation. Endothelins, which are regulated by AgII and TGF-β1, are key factors in fibroblast collagen turnover [1,27,28]. Angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), loop diuretics, spironolactone, and beta-blockers may exert part of their effects through modulation of cardiac extracellular matrix turnover [4,29]. Consequently, these drugs, commonly used among heart failure patients, could have biased our results. However, in our study we did not find any difference in PIP levels with regard to drug therapy. In our study, no correlation was found between PIP levels and ejection fraction or left ventricular end-systolic diameter. Serum PIP has been correlated not only with echocardiographic left ventricular mass index in patients with hypertensive heart disease but also with progression of left ventricular dilatation in dilated myocardiopathy. In this context, our findings may suggest that PIP is involved in the pathophysiology of heart failure, independent of the degree of LVEF preservation or left ventricular mass index. Given the limitations of echocardiography in the assessment of diastolic LV dysfunction, we could not include these results in our study. There are some limitations to our study. Mean concentrations of PIP between patients who reached primary endpoints and those who did not are widely dispersed and, as a result, there is some overlap between the two groups of patients. Therefore, as with other biological markers, a single PIP value from individual patients must be interpreted with caution. We determined PIP using an ELISA assay since it has great feasibility in most hospitals. As such, our results may not be comparable to those published using PIP measurement by radioimmunoassay. Because some drugs, such as ACEI, ARB, aldosterone antagonists, and betablockers, can modify neurohormone levels, we did not evaluate neurohormones or aldosterone levels. Only one case of sudden death was registered. As a result, differences in PIP levels between sudden and progressive death cannot be established. As with other biomarkers, single measurements of PIP in patients with decompensated heart failure have important limitations. PIP should probably be interpreted
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along with other markers, such as natriuretic peptides (either BNP or NT-proBNP), hepatocyte growth factor (HGF), cytokines, CRP, etc.; this would enable us to gain some insight into prognosis and pathophysiology at the same time [30,31]. We highlight several points about PIP in heart failure. First, PIP is a molecule of collagen type I synthesis. Second, PIP is useful in monitoring the process of cardiac fibrosis. Because this process is related to systolic and diastolic dysfunction, PIP could be useful in evaluating clinical progression of heart failure. In conclusion, a single serum PIP measurement in patients with decompensated heart failure seems to have prognostic value since patients with higher values are those with a higher risk of death and readmission. PIP would appear to be a useful tool for screening heart failure patients with an increased risk of complications. Other studies correlating PIP and P-BNP levels with clinical outcomes are ongoing. 5. Learning points • PIP is a molecule of collagen type I synthesis. • PIP is useful in monitoring the process of cardiac fibrosis. • PIP could be useful in evaluating the clinical progression of heart failure. Acknowledgements We are indebted to the Internal Medicine and Immunology Department nurses, Flor Ferreira and Elias Rubio, for their invaluable assistance. This work was supported by grants from Roche Laboratories (Pharmaceutical Division) and managed by Unidad Mixta de Investigacion (Universidad de Zaragoza, Spain) with project number 1131. References [1] Weber KT. Extracellular matrix remodeling in heart failure. Circulation 1997;96:4065–82. [2] Pfefer MA, Braunwald E. Ventricular remodelling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990;81:1161–72. [3] Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation 2000;102:IV-14–23. [4] Zannad F, Dousset B, Alla F. Treatment of congestive heart failure. Interfering the aldosterone–cardiac extracellular matrix relationship. Hypertension 2001;38:1227–32. [5] Weber KT. Monitoring tissue repair and fibrosis from a distance. Circulation 1997;96:2488–92. [6] Rodriguez-Artalejo F, Guallar-Castillon P, Banegas JR, Del Rey J. Trends in hospitalization and mortality for heart failure in Spain, 1980– 1993. Eur Heart J 1997;18:1771–9. [7] Croft JB, Giles WH, Pollard RA, Keenan NL, Casper ML, Anda RF. Heart failure survival among older adults in the United States: a poor prognosis for an emerging epidemic in the Medicare population. Arch Intern Med 1999;159:505–10. [8] Uusimaa P, Risteli J, Niemela M, Lumme J, Ikaheimo M, Jounela A, et al. Collagen scar formation after acute myocardial infarction: relationship to infarct size, left ventricular function, and coronary artery patency. Circulation 1997;96:2565–72.
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[9] Sato Y, Kataoka K, Matsumori A, Sasayama S, Yamada T, Ito H, et al. Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy. Heart 1997;78:505–8. [10] Klappacher G, Franzen P, Haab D, Mehrabi M, Binder M, Plesch K, et al. Measuring extracellular matrix turnover in the serum of patients with idiopatihic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol 1995;75:913–8. [11] Rossi A, Cicoira M, Golia G, Zanolla L, Franceschini L, Marino P, et al. Amino-terminal propeptide of type III procollagen is associated with restrictive mitral filling pattern in patients with dilated cardiomyopathy: a possible link between diastolic dysfunction and prognosis. Heart 2004;90:650–4. [12] Host NB, Jensen LT, Bendixen PM, Jensen SE, Koldkjaer OG, Simonsen EE. The aminoterminal propeptide of type III procollagen provides new information on prognosis after acute myocardial infarction. Am J Cardiol 1995;76:869–73. [13] Cicoira M, Rossi A, Bonapace S, Zanolla L, Golia G, Franceschini L, et al. Independent and additional prognostic value of aminoterminal propeptide of type III procollagen circulating levels in patients with chronic heart failure. J Card Fail 2004;10:403–11. [14] Poulsen SH, Host NB, Egstrup K. Long-term changes in collagen formation expressed by serum carboxyterminal propeptide of type-I procollagen and relation to left ventricular function after acute myocardial infarction. Cardiology 2001;96:45–50. [15] Querejeta R, Lopez B, Gonzalez A, Sanchez E, Larman M, Martinez Ubago JL, et al. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation 2004;110:1263–8. [16] Schwartzkopff B, Fassbach M, Pelzer B, Brehm M, Strauer BE. Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy. Eur J Heart Fail 2002;4:439–44. [17] Shamsham F, Mitchell J. Essentials of the diagnosis of heart failure. Am Fam Physician 2000;61:1319–28. [18] Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000;101:2118–21. [19] Alonso-Martinez JL, Llorente-Diez B, Echegaray-Agara M, OlazPreciado F, Urbieta-Echezarreta M, Gonzalez-Arencibia C. C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail 2002;4:331–6. [20] Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 1998;31:391–8. [21] Sharma R, Rauchhaus M, Ponikowski PP, Varney S, Poole-Wilson PA, Mann DL, et al. The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2000;36:523–8. [22] Kirk V, Bay M, Parner J, Krogsgaard K, Herzog TM, Boesgaard S, et al. N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure study (CHHF). Eur J Heart Fail 2004;6:335–41. [23] Alehagen U, Lindstedt G, Levin LA, Dahlstrom U. Risk of cardiovascular death in elderly patients with possible heart failure. B-type natriuretic peptide (BNP) and the aminoterminal fragment of ProBNP (N-terminal proBNP) as prognostic indicators in a 6-year follow-up of a primary care population. Int J Cardiol 2005;100:125–33. [24] Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma amino terminal brain natriuretic peptide (N-BNP) levels improves results. Lancet 2000;355:1126–30. [25] Pauschinger M, Knopf D, Petschauser S, Doerner A, Poller W, Schwimmbeck PL, et al. Dilated cardiomyopathy is associated with
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significant changes in collagen type I/III ratio. Circulation 1999;99: 2750–6. [26] Boluyt MO, O´Neill L, Meredith AL, Bing OH, Brooks WW, Conrad CH, et al. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure: marked upregulation of genes encoding extracellular matrix components. Circ Res 1994;75: 23–32. [27] Guarda E, Katwa LC, Myers PR, Tyagi SC, Weber KT. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc Res 1993;27:2130–4. [28] Brenner DA, Rippe RA, Rhodes K, Trotter JF, Breindl M. Fibrogenesis and type I collagen gene regulation. J Lab Clin Med 1994;124:755–60.
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Original article
Propeptide of procollagen type I (PIP) and outcomes in decompensated heart failure ☆ Francisco J. Ruiz-Ruiz a , Fernando José Ruiz-Laiglesia a , Pilar Samperiz-Legarre a , Pilar Lasierra-Diaz b , Álvaro Flamarique-Pascual a , José L. Morales-Rull a , Juan I. Perez-Calvo a,⁎ a
Internal Medicine Department, Hospital Clínico Universitario “Lozano Blesa”, Avenida San Juan Bosco, 15, Zaragoza 50009, Spain b Immunology Department, Hospital Clínico Universitario “Lozano Blesa”, Avenida San Juan Bosco, 15, Zaragoza 50009, Spain Received 6 April 2006; received in revised form 25 July 2006; accepted 19 September 2006
Abstract Background: Changes in extracellular matrix are recognized as a contributing factor in the cardiac remodeling process. Several studies have addressed the value of turnover markers of collagen as predictors of death or new heart failure episodes. The aim of the present study was to evaluate the relationship between peripheral serum concentration of propeptide of procollagen type I (PIP) and outcomes in patients with decompensated heart failure. Methods: A total of 111 patients admitted to our Unit between September 2000 and May 2003 for decompensated heart failure were analyzed. Death from any cause or due to heart failure and readmission were considered primary endpoints. Results: The mean PIP concentration was 80.84 ± 36.40 ng/mL. The PIP serum level was significantly higher among those patients who suffered some endpoint during follow-up (88.12 ± 37.31 ng/mL vs 73.13 ± 34.06 ng/mL; p = 0.029). Twenty-five (22.52%) of the 111 patients died during the 21 months of follow-up, and 54 (48.6%) were readmitted with new bouts of heart failure. Using Cox proportional hazards regression analyses, serum PIP levels, systolic dysfunction, and diabetes mellitus were identified as independent predictors of death. Serum PIP levels, age, and sex were independent predictors of new heart failure episodes and readmission. Conclusion: A single serum measurement of PIP seems to have prognostic value in patients with decompensated heart failure. Accordingly, patients with higher values of PIP at decompensation are at a higher risk of death or readmission during follow-up. © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Propeptide of procollagen type I (PIP); Decompensated heart failure; Prognosis
1. Introduction Changes in extracellular matrix, elicited by essential hypertension or myocardial infarction, are recognized as a contributing factor in the cardiac remodeling process.
☆
Data from the manuscript have been presented at the XXVI Congreso Nacional de la Sociedad Española de Medicina Interna. ⁎ Corresponding author. Servicio de Medicina Interna, Hospital Clínico Universitario “Lozano Blesa”, Avenida San Juan Bosco, 15, Zaragoza 50009, Spain. Tel.: +34 976 556 400x2604; fax: +34 976 351 661. E-mail address: [email protected] (J.I. Perez-Calvo).
Myocardial fibrosis contributes to systolic and diastolic ventricular dysfunction and provides the structural substrate for arrythmogenicity, thus potentially contributing to sudden death. Cardiac remodeling is defined by structural changes at the cardiac myocyte level that are translated into alterations in chamber size and geometry. Pressure and volume overload lead to changes in myocardial gene expression of contractile proteins and calcium handling that interfere with contractile function [1–4]. Collagen provides architectural support for the muscle cells and plays an important role in myocardial function. Molecules of synthesis and degradation of collagen (type I and type III collagen) have been used to monitor the fibrosis
0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2006.09.014
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process [5]. Types I and III are the two major types of collagen present in the myocardium in both normal and diseased myocardial tissue. Normal adult myocardium is governed by a balanced equilibrium between stimulator and inhibitor signals (such as prostaglandins, endothelin, bradykinin, angiotensin, transforming growth factor, nitric oxide, or aldosterone) that regulate cell growth, apoptosis, and collagen turnover. In heart failure, a complex series of molecular events that include the expression of genes and activation of multiple second messenger system alter the composition of the extracellular matrix. The prognosis of heart failure is bleak and may be worse than that for most types of cancer [6,7]. Several studies have addressed the value of turnover markers of collagen as predictors of death or new heart failure episodes. Procollagen type III aminoterminal peptide (PIIINP) has been found to be increased in patients with hypertensive left ventricular hypertrophy, ventricular dysfunction after acute myocardial infarction, or dilated cardiomyopathy [8,9]. Indeed, high serum levels of PIIINP are significantly associated with poor outcome [10–13]. The carboxyterminal propeptide of type I procollagen (PIP), a molecule of collagen synthesis, seems useful in predicting the development of heart failure among patients with acute myocardial infarction or hypertension and might be a valuable marker for progression of left ventricular dilation [14–16]. The aim of the present study was to evaluate the relationship between peripheral serum concentration of PIP and outcomes in elderly patients with decompensated heart failure. 2. Methods 2.1. Patients, study design, procedures, and endpoints One hundred and eleven patients were admitted to our Unit between September 2000 and May 2003 because of decompensated heart failure. Patients with diseases that can modify prognosis, such as neoplasm, severe infection, and Alzheimer's or neurodegenerative disease, were excluded. Patients with alcoholic liver disease, renal insufficiency (creatinine clearance b 20 mL/ min, estimated by Gault–Cockroft equation), hyperthyroidism, or metabolic bone disease were excluded because these diseases can modify the serum concentration of PIP. Patients older than 85 years were also excluded from the study to avoid possible biases on endpoints. Finally, patients who died during the initial (index) hospitalization were also excluded from the analysis. The diagnosis of heart failure was made on the basis of clinical and echocardiographic findings, according to the Framingham and Boston criteria [17]. Acute left heart decompensation was based on an increase in dyspnea or orthopnea, pulmonary rales, or radiographic findings consistent with pulmonary edema. Death from any cause or due to heart failure and readmission were considered primary endpoints.
Blood samples were taken during the first 72 h after clinical admission. Each sample was centrifuged at 3000 rpm for 10 min at 4 °C, separated, and stored at −40 °C until analysis. Serum PIP was determined by ELISA (Procollagen type I Cpeptide EIA kit; precoated; Takara Bio, Inc). The PIP EIA kit is a solid-phase enzyme immunoassay based on a sandwich method that utilizes two mouse monoclonal anti-PIP antibodies to detect PIP by a one-step procedure. The inter-assay and intra-assay variations for determining PIP were 6.3% and 7.4%, respectively. The sensitivity was 10 ng/mL. We selected 25 patients admitted for causes not related to heart disease as a control group. Mean PIP values for controls were 54.03 ± 14.89 ng/mL (range 42.19 to 89.73 ng/mL). Echocardiography was performed during admission on each patient unless it had been performed less than 3 months earlier. According to left ventricular ejection fraction (LVEF) measurement, patients were classified into two groups: those with systolic dysfunction (LVEF b 40%) and those with preserved LVEF (N 40%), according to the Vasan and Levy criteria [18]. Informed consent for the test, stored samples, and review of the records was obtained from all participants. 2.2. Statistical analysis Values are expressed as mean ± SD or percentage, depending on the type of variable. The Statistical Program for the Social Science (SPSS) was used for data entry and processing. Student's t-test was used to test for differences in continuous variables and the χ2 test was used for categorical variables. Receiver-operating-characteristic (ROC) analysis was performed for PIP levels. Long-term survival was assessed from the day of admission to the hospital to the day of death or to 1 March 2004. Cumulative survival curves were constructed according to the Kaplan–Maier method, and differences between curves were tested with the log-rank test. Predictors of new heart failure episodes or death were analyzed by Cox proportional hazards analysis. p values less than 0.05 were considered statistically significant. 3. Results Demographic characteristics of the patients are shown in Table 1. Analyzing the age variable, 12.6% of the patients were younger than 65 and 50% were between 75 and 85 years old. Fifty-five patients (49.5%) had a previous diagnosis of heart failure; 43 of them had been admitted earlier for this reason. Factors triggering decompensation could not be elucidated in 51 patients (45.9%). In such cases, mild viral infection and lack of diet or drug adherence were considered the most probable causes. The mean PIP concentration was 80.84 ± 36.40 ng/mL (range 33.94 to 244.88 ng/mL). There were no differences in PIP concentration with regard to age, sex or cause of heart
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Table 1 Clinical characteristics of the population Clinical characteristics
Value
Age (years) Male Prior heart failure Hypertensive etiology Ischemic etiology Other etiologies Systolic dysfunction Heart failure with ejection fraction preserved
73.45 ± 7.95 59 (53.2%) 55 (49.5%) 32 (28.8%) 40 (36.0%) 28 (35.2%) 51 (45.9%) 60 (54.1%)
Echocardiographic parameters Ejection fraction (%) End-systolic diameter of left ventricle (mm) End-diastolic diameter of left ventricle (mm) Previous treatment with ACE inhibitors or ARB
49.7 ± 15.3 37.4 ± 10.9 53.9 ± 9.6 51 (45.9%)
Associated diseases Diabetes Hypertension Chronic obstructive pulmonary disease
34 (30.6%) 60 (54.1%) 25 (22.5%)
NYHA: New York Heart Association. ACE: angiotensin-converting enzyme. ARB: angiotensin receptor blockers.
failure. There was no correlation between serum PIP levels and LVEF. All patients admitted were in class III or IVof the New York Heart Association (NYHA). For analytical purposes, we considered basal functional class, according to the NYHA. Consequently, patients in basal class III or IVof the NYHA had higher concentrations than those in basal class I or II of the NYHA (97.26 ± 46.48 ng/mL vs 77.46 ± 38.70 ng/mL), but the difference was not statistically significant (p = 0.082). Among the 54 patients with some primary endpoints at follow-up (new hospitalizations or death), PIP levels were higher than in the 57 patients without them (88.12 ± 37.31 ng/ mL vs 73.13 ± 34.06 ng/mL; p = 0.029). Twenty-five of the 111 patients (22.52%) died during the 21 months of follow-up. In 22 (19.82%), the cause of death was related to heart failure. Three additional patients died of non-related causes and 86 remained alive.
Fig. 2. Curves showing patients who were readmitted due to new heart failure episodes. The broken line shows patients with serum PIP levels above 124 ng/mL.
Fifty-four patients (48.6%) were readmitted to the hospital with new bouts of heart failure. Some 26 patients were readmitted once, 15 patients twice, 7 patients three times, and 6 patients more than three times. A weak correlation between serum PIP levels and number of new episodes of heart failure was found (r = 0.26, p = 0.006). During follow-up, patients with a lower serum PIP concentration fared significantly better than those with a higher serum PIP concentration (mean survival 1090 vs 449 days). A PIP level above 124 ng/mL was predictive of death (log-rank test, p b 0.001) and new heart failure episodes (log-rank test, p b 0.003), according to the Kaplan–Maier survival method (Figs. 1 and 2). There were no differences in mortality and/or new episodes of heart failure according to etiology or comorbidity (including diabetic and non-diabetic patients). Using Cox proportional hazards regression analyses (Table 2), serum PIP levels, systolic dysfunction, and diabetes mellitus were identified as independent predictors of death. Serum PIP levels, age, and sex were independent predictors of new heart failure episodes and readmission.
Table 2 Predictors of death or the need for readmission due to heart failure during follow-up (multivariate analysis)
Fig. 1. Mortality curves illustrating deaths due to heart failure. The broken line shows patients with serum PIP levels above 124 ng/mL.
Variable
Readmission due to heart failure
Death due to heart failure
OR
OR
Age Sex (male) Diabetes mellitus Systolic dysfunction Serum PIP levels
1.059 1.006–1.115 0.028 1.002 0.920–1.092 0.960 2.079 1.078–4.000 0.029 1.960 0.618–6.211 0.252 1.416 0.874–2.881 0.336 6.535 1.773–23.80 0.005
95% CI
p
95% CI
p
1.540 0.793–2.994 0.202 3.623 1.079–12.19 0.037 1.015 1.006–1.024 0.001 1.036 1.017–1.055 0.001
OR: odds ratio. CI: confidence intervals.
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The area under the ROC for readmissions due to new heart failure episodes was 0.647 (95% CI 0.545–0.75) and it was 0.659 (95% CI 0.527–0.791) for death due to heart failure. ROC curves for various PIP cut-off values were calculated. A cut-off value of 124 ng/mL predicted prognosis most accurately. 4. Discussion Heart failure is a major health problem in developed countries and accounts for a large proportion of hospital admissions and deaths. Early diagnosis and correct therapy are key factors to reducing morbidity and mortality in such patients. Certain biochemical markers and neurohormones have prognostic value for patients with heart failure. Creactive protein (CRP), interleukin-6 (IL-6), and erythrocyte sedimentation rate (ESR) have been studied in heart failure, but with different results [19–21]. B-type natriuretic peptides (BNP and NT-proBNP) serve for risk stratification in large groups of patients suffering from heart failure [22,23]. Strategies based on BNP-guided therapy have been shown to be more efficient than those relying exclusively on clinical findings among patients with heart failure [24]. Accordingly, identification of biochemical markers, and especially their correlation with clinical outcomes, can help to identify groups of patients at a higher risk of complications or those who need a stricter follow-up and/or an intensified drug therapy. Several studies have addressed the role of molecule degradation of collagen type I (ICTP) in heart failure. Klappacher et al. showed that levels of PIIINP and ICTP were independent predictors of mortality [10]. Patients with higher circulating levels of extracellular matrix proteins were those at an increased relative risk of advanced clinical stage hyponatremia, poor hemodynamic condition, heart transplantation, and death during followup, as compared to patients with lower circulating levels. Collagen type I is characterized by strength and stiffness, whereas collagen type III is characterized by elasticity. Pauschinger et al. reported an increase in the collagen type I/III ratio in patients with dilated cardiomyopathy, something that would reflect an increasing myocardial stiffness, compromising diastolic and systolic function of the myocardium [25]. In our series, PIP was measured in 111 patients admitted for acutely decompensated chronic heart failure. The group, as a whole, is representative of the spectrum of patients admitted in current clinical practice. In our study, serum PIP levels showed a significant correlation with clinical outcome at 21 months. A PIP cut-off value of 124 pg/mL identified those patients who had a greater probability of death and new admissions at follow-up. Decompensated heart failure has been associated with increased mRNA expression of matrix proteins (types I and III collagen) and encoded proteins [26]. The results of our study are in keeping with these findings and support the
notion that the increase in serum markers of collagen synthesis might correlate with clinical outcome. Myocardial fibrosis is the consequence of either increased collagen synthesis or decreased extracellular matrix degradation. It has been involved in left ventricular dysfunction in patients with both systolic and diastolic dysfunction. Hemodynamic and non-hemodynamic factors have been involved in such an imbalance. Neurohormones, cytokines, and drugs play a role in myocardial fibrosis [1]. A close relationship between angiotensin II (AgII) and profibrotic cytokines represented by peptides belonging to the transforming growth factor beta (TGF-β) family has been suggested. Accordingly, binding of TGF-β 1 to their receptors on fibroblasts regulates the expression of type I collagen and favors fibrous tissue formation. Endothelins, which are regulated by AgII and TGF-β1, are key factors in fibroblast collagen turnover [1,27,28]. Angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), loop diuretics, spironolactone, and beta-blockers may exert part of their effects through modulation of cardiac extracellular matrix turnover [4,29]. Consequently, these drugs, commonly used among heart failure patients, could have biased our results. However, in our study we did not find any difference in PIP levels with regard to drug therapy. In our study, no correlation was found between PIP levels and ejection fraction or left ventricular end-systolic diameter. Serum PIP has been correlated not only with echocardiographic left ventricular mass index in patients with hypertensive heart disease but also with progression of left ventricular dilatation in dilated myocardiopathy. In this context, our findings may suggest that PIP is involved in the pathophysiology of heart failure, independent of the degree of LVEF preservation or left ventricular mass index. Given the limitations of echocardiography in the assessment of diastolic LV dysfunction, we could not include these results in our study. There are some limitations to our study. Mean concentrations of PIP between patients who reached primary endpoints and those who did not are widely dispersed and, as a result, there is some overlap between the two groups of patients. Therefore, as with other biological markers, a single PIP value from individual patients must be interpreted with caution. We determined PIP using an ELISA assay since it has great feasibility in most hospitals. As such, our results may not be comparable to those published using PIP measurement by radioimmunoassay. Because some drugs, such as ACEI, ARB, aldosterone antagonists, and betablockers, can modify neurohormone levels, we did not evaluate neurohormones or aldosterone levels. Only one case of sudden death was registered. As a result, differences in PIP levels between sudden and progressive death cannot be established. As with other biomarkers, single measurements of PIP in patients with decompensated heart failure have important limitations. PIP should probably be interpreted
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along with other markers, such as natriuretic peptides (either BNP or NT-proBNP), hepatocyte growth factor (HGF), cytokines, CRP, etc.; this would enable us to gain some insight into prognosis and pathophysiology at the same time [30,31]. We highlight several points about PIP in heart failure. First, PIP is a molecule of collagen type I synthesis. Second, PIP is useful in monitoring the process of cardiac fibrosis. Because this process is related to systolic and diastolic dysfunction, PIP could be useful in evaluating clinical progression of heart failure. In conclusion, a single serum PIP measurement in patients with decompensated heart failure seems to have prognostic value since patients with higher values are those with a higher risk of death and readmission. PIP would appear to be a useful tool for screening heart failure patients with an increased risk of complications. Other studies correlating PIP and P-BNP levels with clinical outcomes are ongoing. 5. Learning points • PIP is a molecule of collagen type I synthesis. • PIP is useful in monitoring the process of cardiac fibrosis. • PIP could be useful in evaluating the clinical progression of heart failure. Acknowledgements We are indebted to the Internal Medicine and Immunology Department nurses, Flor Ferreira and Elias Rubio, for their invaluable assistance. This work was supported by grants from Roche Laboratories (Pharmaceutical Division) and managed by Unidad Mixta de Investigacion (Universidad de Zaragoza, Spain) with project number 1131. References [1] Weber KT. Extracellular matrix remodeling in heart failure. Circulation 1997;96:4065–82. [2] Pfefer MA, Braunwald E. Ventricular remodelling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990;81:1161–72. [3] Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation 2000;102:IV-14–23. [4] Zannad F, Dousset B, Alla F. Treatment of congestive heart failure. Interfering the aldosterone–cardiac extracellular matrix relationship. Hypertension 2001;38:1227–32. [5] Weber KT. Monitoring tissue repair and fibrosis from a distance. Circulation 1997;96:2488–92. [6] Rodriguez-Artalejo F, Guallar-Castillon P, Banegas JR, Del Rey J. Trends in hospitalization and mortality for heart failure in Spain, 1980– 1993. Eur Heart J 1997;18:1771–9. [7] Croft JB, Giles WH, Pollard RA, Keenan NL, Casper ML, Anda RF. Heart failure survival among older adults in the United States: a poor prognosis for an emerging epidemic in the Medicare population. Arch Intern Med 1999;159:505–10. [8] Uusimaa P, Risteli J, Niemela M, Lumme J, Ikaheimo M, Jounela A, et al. Collagen scar formation after acute myocardial infarction: relationship to infarct size, left ventricular function, and coronary artery patency. Circulation 1997;96:2565–72.
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