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Chronic heart failure patients with high collagen type I degradation marker levels benefit more with ACE-inhibitor therapy
European Journal of Pharmacology 628 (2010) 164–170
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European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r
Cardiovascular Pharmacology
Chronic heart failure patients with high collagen type I degradation marker levels benefit more with ACE-inhibitor therapy Sofia V. Chatzikyriakou a, Dimitrios N. Tziakas a,⁎, Georgios K. Chalikias a, Dimitrios Stakos a, Adina Thomaidi a, Konstantina Mitrousi a, Harisios Boudoulas b a b
University Cardiology Department, Medical School, Democritus University of Thrace, Alexandroupolis, Greece Center for Clinical Research, Foundation of Biomedical Research, Academy of Athens, Athens, Greece
a r t i c l e
i n f o
Article history: Received 7 May 2009 Received in revised form 12 November 2009 Accepted 23 November 2009 Available online 1 December 2009 Keywords: Angiotensin converting enzyme-inhibitor Collagen metabolism Prognosis Chronic heart failure
a b s t r a c t Not all patients respond to angiotensin converting enzyme (ACE)-inhibitor equally. Genetic or other phenotypic variations might be useful in predicting the therapeutic efficacy of these drugs. With the present study we assessed the prognostic impact of ACE-inhibitor in chronic heart failure patients with different degrees of collagen metabolism as assessed by serum levels of a collagen type I degradation marker (CITP). One hundred ninety-six (126 male, 69± 10 years) chronic heart failure patients were studied prospectively for 12 months regarding survival. Serum concentrations of CITP were measured at study entry. Chronic heart failure patients were divided into groups according to whether (n = 114) or not (n = 82) they received ACE-inhibitor as well as to their CITP levels. Survival (52.2%) was significantly lower in ACE-inhibitor naive patients with high CITP levels compared to ACE-inhibitor naive patients with low CITP levels (83.3%, P = 0.003), to ACE-inhibitor users with low CITP levels (80%, P = 0.006) and to ACE-inhibitor users with high CITP levels (70.4%, P = 0.015). ACE-inhibitor related improvement in mortality was most predominant in chronic heart failure patients with high CITP levels. CITP levels possibly reflecting an activated status of the renin–angiotensin–aldosterone system, may be of clinical relevance since they identify a subgroup of patients that is more susceptible to treatment with an ACE-inhibitor. © 2009 Elsevier B.V. All rights reserved.
1. Introduction The effectiveness of angiotensin converting enzyme (ACE)-inhibitors in improving survival of patients with chronic heart failure has been reported from recent large-scale clinical trials (Garg and Yusuf, 1995). However, despite optimized treatment with ACE-inhibitors, a group of patients with chronic heart failure is characterized by a greater benefit in survival (Van de Wal et al., 2006; Roig et al., 2000). This observation suggests that not all patients respond to ACE-inhibitors equally (Dickerson et al., 1999; Struthers et al., 2001), and therefore it has been postulated that genetic or other phenotypic variations might be useful in predicting the therapeutic efficacy of these drugs (Jan Danser et al., 2007). There is accumulating data showing that angiotensin modulates collagen synthesis and degradation (Gonzalez et al., 2002). This evidence has supported the concept that beneficial effects of ACEinhibitors on prognosis in these patients are related, at least in part, to their effects on myocardial remodelling and especially on collagen metabolism and fibrosis (Landmesser et al., 2009; Zannad and Radauceanu, 2005; Fleming, 2006).
⁎ Corresponding author. Voulgaroktonou 23, 68100 Alexandroupolis, Greece. Tel.: +30 25510 35596(home), +30 25510 76205(office); fax: +30 25510 76245. E-mail address: [email protected] (D.N. Tziakas). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.11.047
In addition, non-invasive measurement of collagen-derived serum peptides has been proposed as a useful tool to address myocardial fibrosis from a distance (Weber, 1997; Zannad et al., 2001). Recent studies have also shown that collagen turnover—as assessed with serological markers—is altered in chronic heart failure and has an impact on prognosis (Klappacher et al., 1995; Kitahara et al., 2007; Zannad et al., 2000). In specific high collagen type I degradation levels were negatively associated with survival (Klappacher et al., 1995; Kitahara et al., 2007; Zannad et al., 2000). We hypothesized that the extent of collagen metabolism, as assessed by serum levels of a collagen type I degradation marker, would provide insight into the impact that ACE-inhibitor treatment has on survival in chronic heart failure patients. 2. Material and methods 2.1. Patients We prospectively studied 207 consecutive patients, who were admitted to the Coronary Care Unit, Department of Cardiology, with acute decompensation of chronic heart failure. The chronic heart failure status had been determined on a prior visit to our Outpatient Heart Failure Clinic. Patients were followed for up to 12 months after admission using a standardized protocol that included outpatient visits and telephone
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contacts. Follow up contacts were focused on the recording of ACEinhibitor treatment adherence. Patients who discontinued ACEinhibitor therapy (n = 6) were excluded. Furthermore, patients who failed to attend follow up visits (n = 3) or had incomplete follow up data (n = 2) were also excluded from further analysis. The remaining 196 patients (126 male, mean age 69 ± 10 years) constituted the study group. The endpoint of the study was cardiac death defined as death from worsening heart failure or sudden cardiac death.
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Chronic heart failure patients were divided into groups according to whether or not they received ACE-inhibitor therapy. Since treatment of study participants was in agreement with current published guidelines, restraining patients from ACE-inhibitor therapy was solely based on specific treatment contraindications/side-effects (Dickstein et al., 2008). Although chronic heart failure patients who were not on ACE-inhibitors fulfilled similar diagnostic criteria as chronic heart failure patients receiving such therapy (Table 1), they were more likely to have
Table 1 Comparison of baseline characteristics between angiotensin converting enzyme (ACE)-inhibitor treated and naive chronic heart failure patients. Variable
ACE-inhibitor naive patients n = 82
ACE-inhibitor treated patients n = 114
P
Age, years Male/Female, n Systolic blood pressure, mm Hg Heart rate, bpm QRS duration, s Body mass index (kg/m2)
68 (65–70) 52/30 120 (113–127) 84 (80–88) 0.11 (0.10–0.12) 29 (28–30)
68 (66–70) 74/40 146 (141–151) 74 (71–77) 0.10 (0.09–0.11) 30 (29–31)
0.812 0.880 b0.001a b0.001a 0.143 0.267
NYHA classification, n (%) II III IV
22 (27%) 42 (51%) 18 (22%)
42 (37%) 60 (53%) 12 (10%)
Etiology, n (%) Coronary artery disease Hypertensive cardiomyopathy Valve disease Idiopathic dilated cardiomyopathy
34 14 14 20
(42%) (17%) (17%) (24%)
50 (44%) 34 (30%) 16 (14%) 14 (12%)
Co-morbidities, n (%) Diabetes mellitus Hypertension Atrial fibrillation Smoking Respiratory disease
32 46 36 14 34
(39%) (56%) (44%) (17%) (41%)
52 (46%) 78 (68%) 54 (47%) 26 (23%) 38 (33%)
0.383 0.098 0.665 0.372 0.244
Echocardiographic findings Preserved systolic function, n (%) Left ventricular mass, g Left ventricular ejection fraction, %
12 (15%) 387 (360–414) 36 (34–39)
36 (32%) 412 (381–442) 42 (40–45)
0.007b 0.600 0.002a
Treatment during follow up, n (%) b-Blockers Diuretics Aldosterone antagonists Digitalis Nitrates Angiotensin receptor blockers Calcium channel blockers Amiodarone Statins Aspirin Clopidogrel Anticoagualants
12 82 26 32 44 20 16 12 26 34 16 30
26 (23%) 114 (100%) 38 (33%) 56 (49%) 58 (51%) 6 (5%) 30 (26%) 12 (11%) 48 (42%) 62 (54%) 12 (11%) 54 (48%)
Biochemical markers Hemoglobin, g/dl White blood count, x103/μl Creatinine, mg/dl Sodium, mg/dl Uric acid, mg/dl Albumin, g/dl Total cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 CRP, mg/dl CITP, ng/ml NT-proBNP, pg/ml
12.9 (12.6–13.3) 8.6 (8–9.2) 1.3 (1.2–1.4) 140 (139–142) 7.7 (7.3–8) 6.8 (6.7–6.9) 162 (150–173) 44 (41–46) 124 (108–139) 67 (61–72) 1.6 (1.3–2) 0.55 (0.44–0.66) 6327 (4100–8554)
0.062
0.056
(15%) (100%) (32%) (40%) (54%) (24%) (20%) (15%) (32%) (42%) (20%) (37%)
13.3 (13–13.6) 8.7 (8.3–9.2) 1.2 (1.2–1.3) 142 (141–142) 7.6 (7.3–7.9) 6.7 (6.6–6.8) 173 (164–182) 45 (43–48) 142 (114–170) 69 (64–73) 1.6 (1.3–2) 0.43 (0.37–0.49) 2723 (2141–3306)
0.200 1.000 0.878 0.242 0.772 b0.001b 0.308 0.388 0.179 0.083 0.098 0.145
0.084 0.746 0.314 0.059 0.808 0.543 0.120 0.480 0.311 0.591 0.460 0.034a 0.003a
Values are expressed as means and 95% CI for continuous variables and as number of patients and % for categorical variables. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I, CRP; C-reactive protein, HDL; high density lipoprotein, NTproBNP; N-terminal propeptide of brain natriuretic peptide, and NYHA; New York Heart Association. a For unpaired Student's t-test. b For chi-square test.
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contraindications for ACE-inhibitor use, i.e. hypotension, history of drug related-cough, and history of angioedema (Dickstein et al., 2008). Peripheral blood samples were obtained from all patients at discharge after resolution of symptoms and restoration of a clinical stable status. The compensated chronic heart failure status was documented by the absence of dyspnoea at rest, orthopnoea and body weight close to their known dry body weight, the absence of pulmonary rales, third heart sound, and leg oedema on clinical examination and the absence of pulmonary venous congestion on chest radiography. Furthermore, after resolution of symptoms an echocardiography study was performed using standard techniques (Cheitlin et al., 1997), in which left ventricular ejection fraction and left ventricular mass were assessed (Feigenbaum et al., 2005). Exclusion criteria were (1) acute decompensation of chronic heart failure due to acute medical illness, acute coronary syndrome, severe aortic stenosis, hypertrophic cardiomyopathy and excessive alcohol intake and (2) renal insufficiency (plasma creatinine N 2 mg/dl), liver, autoimmune, thyroid, bone, haematological, lung, neoplastic disease and major trauma or surgery in the last 3 months. All subjects gave written informed consent, and were studied in compliance with ethical approval and were on standard medical treatment for heart failure.
2.2. Biochemistry analysis Samples were drawn from a peripheral vein of the patients and after centrifugation at 4000 rpm for 10 min, serum samples were frozen and stored at −70 °C until use. Serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) were measured by commercially available immunoassays (ELECSYS 1010, Roche Diagnostics Ltd, Switzerland). Minimum detectable concentration of CITP was b0.01 ng/ml with intra-assay and inter-assay of 4.6% and 4.7% respectively.
3. Results Table 2 summarizes the baseline characteristics of study participants. There were 56 cardiac deaths during follow up. The mean observation period for survival was 322 ± 90 days. Cumulative event-
Table 2 Baseline characteristics of study population. Variable
All study participants n = 196
Age, years Male/Female, n Systolic blood pressure, mm Hg Heart rate, bpm QRS duration, sec Body mass index (kg/m2)
68 (66–69) 126/70 139 (135–143) 78 (76–81) 0.11 (0.10–0.11) 30 (29–30)
NYHA classification, n (%) II III IV
64 (33%) 102 (52%) 30 (15%)
Etiology, n (%) Coronary artery disease Hypertensive cardiomyopathy Valve disease Idiopathic dilated cardiomyopathy
84 48 30 34
Co-morbidities, n (%) Diabetes mellitus Hypertension Atrial fibrillation Smoking Respiratory disease
84 (43%) 124 (63%) 90 (46%) 40 (20%) 72 (37%)
Echocardiographic findings Preserved systolic function, n (%) Left ventricular mass, g Left ventricular ejection fraction, %
48 (25%) 401 (380–422) 40 (38–42)
Treatment, n (%) ACE-inhibitors b-Blockers Diuretics Aldosterone antagonists Digitalis Nitrates Angiotensin receptor blockers Calcium channel blockers Amiodarone Statins Aspirin Clopidogrel Anticoagualants
Pre study entry 124 (63%) 46 (24%) 164 (84%) 44 (22%) 76 (39%) 70 (36%) 26 (13%) 44 (22%) 8 (4%) 56 (29%) 86 (44%) 30 (15%) 50 (26%)
Biochemical markers Hemoglobin, g/dl White blood count, x103/μl Creatinine, mg/dl Sodium, mg/dl Uric acid, mg/dl Albumin, g/dl Total cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 CRP, mg/dl CITP, ng/ml NT-proBNP, pg/ml
13.2 (12.9–13.4) 8.7 (8.3–9) 1.2 (1.2–1.3) 141 (140–142) 7.6 (7.4–7.9) 6.8 (6.7–6.8) 168 (161–175) 44 (43–46) 134 (117–152) 68 (64–71) 1.6 (1.4–1.9) 0.48 (0.42–0.54) 4231 (3220–5243)
(43%) (25%) (15%) (17%)
2.3. Statistical analysis Statistical analyses were performed with SPSS 15 (SPSS Inc., Chicago, Illinois). Statistical analyses consisted of an evaluation of baseline serum CITP levels as predictors of survival, and testing the relationship between baseline CITP levels and survival benefit from ACE-inhibitor use. Association between CITP levels and survival was analyzed by using marker values as a categorical variable with a cutoff value the median of its distribution. Results are presented as means with 95% confidence intervals (CI) for continuous variables and as percentages for categorical data. Normality was tested using Kolmogorov–Smirnov test. Creatinine, sodium, total-, high density lipoprotein- (HDL-) cholesterol, C-reactive protein (CRP), triglycerides, CITP and N-terminal propeptide of brain natriuretic peptide (NT-proBNP) levels as well as QRS duration and left ventricular mass were not normally distributed and were therefore logarithmically transformed as required to approach normal distribution and to obtain equal variances. Comparisons between categorical variables were performed by a chi-square test or Fisher's exact test when required. Differences in continuous variables between two groups were assessed using the unpaired Student's t-test. Univariate and multivariate Cox proportional hazard analyses were performed to determine independent predictors of the study endpoint. Adjusted hazard ratios were assessed in multivariate Cox models using as cofounders variables that on a univariate analysis were shown to be different between under study groups (low CITP vs. high CITP or ACEinhibitors users vs. ACE-inhibitor naive patients). Time-to-event distributions were summarized with Kaplan–Meier curves and compared by the log-rank test. A P valueb 0.05 was considered statistically significant.
During follow up 114 (58%) 38 (19%) 196 (100%) 64 (33%) 88 (45%) 102 (52%) 26 (13%) 46 (24%) 24 (12%) 74 (38%) 96 (49%) 28 (14%) 84 (43%)
Values are expressed as means and 95% CI for continuous variables and as number of patients and % for categorical variables. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I, CRP; C-reactive protein, HDL; high density lipoprotein, NT-proBNP; N-terminal propeptide of brain natriuretic peptide, and NYHA; New York Heart Association.
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free survival rate was 98% at 1 month, 90% at 3 months, 87% at 6 months, 83% at 9 months and 71% at 12 months. Baseline CITP, with a cut-off value of 0.38 ng/ml (median value) was significantly (P = 0.002) and negatively correlated with survival in the whole study population since patients with high CITP levels (N0.38 ng/ml) had a survival rate of 62% compared to patients with low CITP levels (≤0.38 ng/ml) who had a survival rate of 81.2% (Fig. 1). A univariate Cox proportional hazard analysis showed that patients with high CITP levels had a hazard ratio of 2.3 (95% CI 1.3–4, P = 0.004) compared to patients with low CITP levels. In a multivariate Cox model (with cofounders the variables that were different between the two groups, Table 3) patients with high CITP levels had an adjusted hazard ratio of 2 (95% CI 1.1–3.8, P = 0.026) compared to patients with low CITP levels. The study population was then divided in 4 groups based on a CITP median value (0.38 ng/ml) as well as on being under therapy with ACE-inhibitors or not (Group A (n = 36): not on ACE-inhibitors/low CITP levels, Group B (n = 60): on ACE-inhibitors/low CITP levels, Group C (n = 54): on ACE-inhibitors/high CITP levels, and Group D (n = 46): not on ACE-inhibitors/high CITP levels). A Kaplan–Meier survival curve analysis showed that event-free rates were significantly lower in Group D compared to other subgroups (overall P b 0.001, Fig. 2). Specific patients in Group D had a lower survival rate (52.2%) compared to patients of Group A (survival rate 83.3%, P = 0.003), of Group B (survival rate 80%, P = 0.006) and of Group C (survival rate 70.4%, P = 0.015). In contrast, survival rates did not differ between Group A and Group B (P = 0.748) or Group C (P = 0.217). Similarly, survival rates were not significantly different between Groups B and C (P = 0.283). The increased cardiac risk of patients in Group D was preserved in a multivariate Cox proportional hazard model (Table 4). Furthermore, among the subgroup not under ACE-inhibitor therapy (n = 82), patients with high CITP levels (N0.38 ng/ml) compared to patients with low CITP levels (≤0.38 ng/ml) had an adjusted hazard ratio of 2.71 (95% CI 1.17–8.79, P = 0.037). Specifically, patients with high CITP levels had a significantly lower (P = 0.026) survival rate of 52.2% compared to patients with low CITP levels (survival rate of 83.3%) (Fig. 3). In contrast, among the subgroup under ACE-inhibitor therapy (n = 114), baseline CITP levels were not associated with survival (P = 0.604) since patients with high CITP levels had a similar (P = 0.283) survival rate (80%) compared to patients with CITP levels (survival rate of 70.4%). Conversely, among the subgroup with CITP levels above median (N0.38 ng/ml) (n = 100), use of ACE-inhibitors was associated with a survival benefit (adjusted hazard ratio of 0.51 95% CI 0.24–0.07,
Table 3 Comparison of baseline characteristics between patients with high (N0.38 ng/ml) and low carboxy-terminal telopeptide of collagen type I (CITP) (≤ 0.38 ng/ml) levels. Variable
Low CITP levels (n = 96)
High CITP (n= 100)
Age, years Male/Female, n Systolic blood pressure, mm Hg Heart rate, bpm QRS duration, s Body mass index (kg/m2)
67 (65–69) 70/26 142 (137–147)
68 (66–70) 56/44 137 (130–144)
0.389 0.017a 0.260
75 (72–79) 0.11 (0.09–0.11) 31 (30–32)
81 (77–84) 0.11 (0.10–0.12) 28 (27–29)
0.029b 0.358 0.001b
NYHA classification, n (%) II III IV
32 (33%) 52 (54%) 12 (13%)
32 (32%) 50 (50%) 18 (18%)
48 18 12 18
(50%) (19%) (13%) (19%)
36 30 18 16
(36%) (30%) (18%) (16%)
42 56 42 30 35
(44%) (58%) (44%) (31%) (36%)
42 68 48 10 37
(42%) (68%) (48%) (10%) (37%)
Etiology, n (%) Coronary artery disease Hypertensive cardiomyopathy Valve disease Idiopathic dilated cardiomyopathy Co-morbidities, n (%) Diabetes mellitus Hypertension Atrial fibrillation Smoking Respiratory disease Echocardiographic findings Preserved systolic function, n (%) Left ventricular mass, g Left ventricular ejection fraction, %
P
0.560
0.114
0.885 0.183 0.569 b0.001a 0.937
22 (23%)
26 (26%)
0.623
388 (357–419)
414 (385–443)
0.128
39 (37–42)
40 (38–43)
0.640
54 (54%) 16 (16%) 100 (100%) 38 (38%) 42 (43%) 54 (54%) 8 (8%) 30 (30%) 16 (16%) 32 (32%) 42 (42%) 20 (20%) 36 (36%)
0.249 0.279 1.000 0.128 0.564 0.668 0.035a 0.030a 0.128 0.106 0.063 0.024a 0.060
Treatment during follow up, n (%) ACE-inhibitors 60 (63%) b-Blockers 22 (23%) Diuretics 96 (100%) Aldosterone antagonists 26 (27%) Digitalis 46 (48%) Nitrates 48 (50%) Angiotensin receptor blockers 18 (19%) Calcium channel blockers 16 (17%) Amiodarone 8 (8%) Statins 42 (44%) Aspirin 54 (56%) Clopidogrel 8 (8%) Anticoagualants 48 (50%) Biochemical markers Hemoglobin, g/dl White blood count, x103/μl Creatinine, mg/dl Sodium, mg/dl Uric acid, mg/dl Albumin, g/dl Total cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 CRP, mg/dl NT-proBNP, pg/ml
Fig. 1. A Kaplan–Meier analysis of cardiac event-free rates among whole study population (n = 196) stratified into subgroups based on carboxy-terminal telopeptide of collagen type I (CITP) levels. Low CITP levels (≤0.38 ng/ml): black line. High CITP levels (N 0.38 ng/ml): grey line. CITP; carboxy-terminal telopeptide of collagen type I.
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13.3 (13–13.6) 8.8 (8.3–9.4) 1.2 (1.2–1.3) 141 (141–142) 7.6 (7.3–8) 6.8 (6.7–6.9) 178 (168–188) 46 (44–49) 157 (123–192) 74.2 (68.9–79.5)
13 (12.7–13.3) 8.6 (8.1–9.1) 1.3 (1.2–1.3) 141 (140–142) 7.6 (7.3–7.9) 6.7 (6.6–6.9) 159 (149–168) 43 (40–45) 112 (103–121) 61.8 (57.4–66.2)
1.4 (1.2–1.6) 1.9 (1.5–2.3) 3399 (2261–4538) 5030 (3370–6689)
0.174 0.462 0.313 0.642 0.906 0.728 0.005b 0.069 0.004b b0.001b 0.133 0.183
Values are expressed as means and 95% CI for continuous variables and as number of patients and % for categorical variables. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I, CRP; C-reactive protein, HDL; high density lipoprotein, NT-proBNP; N-terminal propeptide of brain natriuretic peptide, and NYHA; New York Heart Association. a For chi-square test. b For unpaired Student's t-test.
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Fig. 2. A Kaplan–Meier analysis of cardiac event-free rates among chronic heart failure patients stratified into subgroups based on carboxy-terminal telopeptide of collagen type I (CITP) levels and angiotensin converting enzyme (ACE)-inhibitor therapy. Group A (n = 36): ACE-inhibitors (−)/low CITP levels (≤ 0.38 ng/ml), (solid black line, ). Group B (n = 60): ACE-inhibitors (+)/low CITP levels (≤0.38 ng/ml), (dotted black line, ). Group C (n = 54): ACE-inhibitors (+)/high CITP levels (N0.38 ng/ml), (dotted grey line, ). Group D (n = 46): ACE-inhibitors (−)/ high CITP levels (N0.38 ng/ml), (solid grey line, ). ACE; angiotensin converting enzyme, CITP; and carboxy-terminal telopeptide of collagen type I.
P = 0.041) while in the subgroup with CITP levels below median (≤0.38 ng/ml) (n = 96) there was no survival benefit (adjusted hazard ratio of 0.59 95% CI 0.19–1.82, P = 0.360) (Fig. 4). 4. Discussion The present study is among the first to demonstrate that serum levels of collagen metabolism may correlate with the level of impact that ACE-inhibitor therapy has on survival in chronic heart failure patients. The main findings of the present study may be summarized as follows: i) chronic heart failure patients with high serum levels of CITP were characterized by worse survival compared to patients with low levels, and ii) the ACE-inhibitor related improvement in mortality was most predominant in chronic heart failure patients with high CITP levels. Findings of our study may be of clinical relevance since a novel approach of tailoring ACE-inhibitor therapy is implied. Not all patients respond to ACE-inhibitors equally (Dickerson et al., 1999; Struthers et al., 2001). Moreover, several subgroup analyses of large ACE-inhibitor trials have shown that the beneficial treatment effect of ACE-inhibitors is consistent among subgroups of specific clinical characteristics and also is independent of baseline risk (Kazi
Fig. 3. A Kaplan–Meier analysis of cardiac event-free rates among angiotensin converting enzyme-inhibitor naive patients (n = 82) stratified into subgroups based on carboxyterminal telopeptide of collagen type I (CITP) levels. Low CITP levels (≤0.38 ng/ml): black line. High CITP levels (N 0.38 ng/ml): grey line. CITP; carboxy-terminal telopeptide of collagen type I.
and Deswal, 2008; Shekelle et al., 2003). In addition, in the secondary prevention setting, there are no means by which we can guide or tailor ACE-inhibitor therapy. A hypothesis has been raised according to which the observed differences in treatment benefit may lay on the differential activation status of the renin–angiotensin–aldosterone system (RAAS) (Hoite, 2003). Increasing evidence strongly supports the notion that angiotensin II influences both fibrillar collagen synthesis and degradation through direct effects on cardiac fibroblasts. Different signalling pathways of the angiotensin type-1 receptor (AT1R) may modulate collagen synthesis such as the MAP/ERK kinase pathway and TGF-b1 signalling pathways (Gonzalez et al., 2002). In addition to collagen synthesis, angiotensin II stimulation of the AT1R has been shown to
Table 4 Multivariate Cox proportional hazard analysis for predicting cardiac events in whole study group.
Group A Group B Group C
Hazard ratio
95% CI
P value
0.36 0.38 0.53
0.14–0.92 0.18–0.82 0.26–0.96
0.035 (overall) 0.033 0.013 0.039
Hazard ratios refer to comparisons with Group D (reference group). Group A (n = 36): ACE-inhibitors (−)/low CITP levels (≤0.38 ng/ml). Group B (n = 60): ACE-inhibitors (+)/low CITP levels (≤0.38 ng/ml). Group C (n = 54): ACE-inhibitors (+)/high CITP levels (N 0.38 ng/ml). Group D (n = 46): ACE-inhibitors (−)/high CITP levels (N 0.38 ng/ml). Systolic blood pressure, heart rate, ejection fraction, angiotensin receptor blockers use, presence of preserved systolic function and NT-proBNP levels (high vs. low) appeared as covariates in the model. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I.
Fig. 4. Adjusted hazard ratios associated with angiotensin converting enzyme-inhibitor (ACE-i) use according to baseline carboxy-terminal telopeptide of collagen type I (CITP) levels. Horizontal lines indicate 95% confidence intervals. CITP median levels = 0.38 ng/ ml. Systolic blood pressure, heart rate, ejection fraction, angiotensin receptor blockers use, presence of preserved systolic function and NT-proBNP levels (high vs. low) appeared as covariates in the model. ACE-i; angiotensin converting enzyme inhibitors, CITP; carboxy-terminal telopeptide of collagen type I, NT-proBNP; and N-terminal propeptide of brain natriuretic peptide.
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regulate collagen degradation by attenuating matrix metalloproteinase (MMP) activity and by enhancing tissue inhibitor (TIMP) production (Gonzalez et al., 2002). Angiotensin II also increases aldosterone secretion, which is known to participate in cardiac fibrosis via enhancing collagen synthesis and deposition through mineralocorticoid receptors (Zannad et al., 2001). Therefore, chronic heart failure patients with increased activation of RAAS are characterized by an excessively altered collagen metabolism and those patients could be associated with a broader clinical benefit with the use of ACE-inhibitors. On the basis of a number of clinical and experimental observations, it has been suggested that the serum concentration of CITP reflects the rate of extracellular degradation of collagen type I (Yamamoto et al., 2002). Myocardial fibrosis has been shown to be accompanied by collagen degradation and MMP activation, suggesting that collagen degradation is a prerequisite for collagen synthesis, accumulation and fibrosis (Jugdutt, 2003). Additionally, myocardial fibrosis seen with chronic heart failure is characterized also with a shift of collagen phenotype from type I to type III (Yamamoto et al., 2002; Jugdutt, 2003). It is possible that degradation of collagen type I associated with the aforementioned collagen phenotype shift to represent a first step of ventricular fibrosis. Therefore, it is logical to hypothesize that increased CITP levels may reflect excessive collagen synthesis and also an activated status of the RAAS. Several studies have addressed the role of molecule degradation of collagen type I (CITP) in heart failure. In agreement to our study, Klappacher et al., have shown the negative prognostic value of high CITP levels in patients with idiopathic or ischemic dilated cardiomyopathy (Klappacher et al., 1995). Kitahara et al., have shown that high CITP levels are associated with adverse cardiac events in chronic heart failure patients with preserved left ventricular systolic function (Kitahara et al., 2007). Findings from our study should be viewed with certain limitations in mind. We assessed the circulating levels of CITP, instead of the more accurate myocardial levels of CITP. Myocardial biopsies however are difficult to perform in vivo and also unethical to perform since it would not contribute to patient care. Additionally, the use of bblockers, angiotensin receptor blockers and aldosterone antagonists may influence serum levels of CITP, since it has been shown that their use is capable of modulating collagen metabolism (Jugdutt, 2003). The use of multivariate regression models, however could account for possible confounders. Not all of our study participants were optimally treated for heart failure. Specifically, ACE-inhibitors (approximate prescription rate of 60%), b-blockers (approximate prescription rate of 20%) and aldosterone antagonists (approximate prescription rate of 30%) were underutilized in our study population, in agreement though with rates reported in large survey trials (Komajda et al., 2003; Cleland et al., 2002). Specifically, the low prescription rates for b-blockers may be attributed to the relatively old age, the high female to male ratio as well as the high prevalence of respiratory disease of our study population (Follath, 2006). Under the same notion, the relatively old age as well as the high prevalence of mild renal disease in our study population may account for the low prescription rates of aldosterone antagonists (Komajda et al., 2003; Cleland et al., 2002). Similarly, old age, high prevalence of mild renal dysfunction and low blood pressure may account for the low usage of angiotensin receptor blockers in ACE-inhibitor intolerant patients. Furthermore, the high rate of nitrate use in our study population, although in keeping with that reported in the EuroHeart Failure Programme (Komajda et al., 2003) may be attributed to the fact that ischemic heart disease—where nitrates are used more often—was common among study participants. It would be of interest to assess if the aforementioned benefit of ACE-inhibitors is still present in optimally treated patients with high CITP levels; however our study was not powered enough to yield significant results in this study subgroup.
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Finally, ACE-inhibitor treatment allocation (treated or not) was based on the presence or not of side-effects/contraindications and not performed in a randomized manner. Although our study was powered enough to detect differences in survival rates between study subgroups, multi-group comparisons and the associated hyper-inflation error may have influence our results. Therefore, extrapolation of the results of this study should be done cautiously. Ιn conclusion, serum collagen type I turnover markers are of predictive value in chronic heart failure patients and specifically high CITP levels are associated with poor survival rates. Furthermore, CITP levels possibly reflecting an activated status of the RAAS, may be of clinical relevance since they identify a subgroup of patients that is more susceptible to treatment with an ACE-inhibitor.
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European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r
Cardiovascular Pharmacology
Chronic heart failure patients with high collagen type I degradation marker levels benefit more with ACE-inhibitor therapy Sofia V. Chatzikyriakou a, Dimitrios N. Tziakas a,⁎, Georgios K. Chalikias a, Dimitrios Stakos a, Adina Thomaidi a, Konstantina Mitrousi a, Harisios Boudoulas b a b
University Cardiology Department, Medical School, Democritus University of Thrace, Alexandroupolis, Greece Center for Clinical Research, Foundation of Biomedical Research, Academy of Athens, Athens, Greece
a r t i c l e
i n f o
Article history: Received 7 May 2009 Received in revised form 12 November 2009 Accepted 23 November 2009 Available online 1 December 2009 Keywords: Angiotensin converting enzyme-inhibitor Collagen metabolism Prognosis Chronic heart failure
a b s t r a c t Not all patients respond to angiotensin converting enzyme (ACE)-inhibitor equally. Genetic or other phenotypic variations might be useful in predicting the therapeutic efficacy of these drugs. With the present study we assessed the prognostic impact of ACE-inhibitor in chronic heart failure patients with different degrees of collagen metabolism as assessed by serum levels of a collagen type I degradation marker (CITP). One hundred ninety-six (126 male, 69± 10 years) chronic heart failure patients were studied prospectively for 12 months regarding survival. Serum concentrations of CITP were measured at study entry. Chronic heart failure patients were divided into groups according to whether (n = 114) or not (n = 82) they received ACE-inhibitor as well as to their CITP levels. Survival (52.2%) was significantly lower in ACE-inhibitor naive patients with high CITP levels compared to ACE-inhibitor naive patients with low CITP levels (83.3%, P = 0.003), to ACE-inhibitor users with low CITP levels (80%, P = 0.006) and to ACE-inhibitor users with high CITP levels (70.4%, P = 0.015). ACE-inhibitor related improvement in mortality was most predominant in chronic heart failure patients with high CITP levels. CITP levels possibly reflecting an activated status of the renin–angiotensin–aldosterone system, may be of clinical relevance since they identify a subgroup of patients that is more susceptible to treatment with an ACE-inhibitor. © 2009 Elsevier B.V. All rights reserved.
1. Introduction The effectiveness of angiotensin converting enzyme (ACE)-inhibitors in improving survival of patients with chronic heart failure has been reported from recent large-scale clinical trials (Garg and Yusuf, 1995). However, despite optimized treatment with ACE-inhibitors, a group of patients with chronic heart failure is characterized by a greater benefit in survival (Van de Wal et al., 2006; Roig et al., 2000). This observation suggests that not all patients respond to ACE-inhibitors equally (Dickerson et al., 1999; Struthers et al., 2001), and therefore it has been postulated that genetic or other phenotypic variations might be useful in predicting the therapeutic efficacy of these drugs (Jan Danser et al., 2007). There is accumulating data showing that angiotensin modulates collagen synthesis and degradation (Gonzalez et al., 2002). This evidence has supported the concept that beneficial effects of ACEinhibitors on prognosis in these patients are related, at least in part, to their effects on myocardial remodelling and especially on collagen metabolism and fibrosis (Landmesser et al., 2009; Zannad and Radauceanu, 2005; Fleming, 2006).
⁎ Corresponding author. Voulgaroktonou 23, 68100 Alexandroupolis, Greece. Tel.: +30 25510 35596(home), +30 25510 76205(office); fax: +30 25510 76245. E-mail address: [email protected] (D.N. Tziakas). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.11.047
In addition, non-invasive measurement of collagen-derived serum peptides has been proposed as a useful tool to address myocardial fibrosis from a distance (Weber, 1997; Zannad et al., 2001). Recent studies have also shown that collagen turnover—as assessed with serological markers—is altered in chronic heart failure and has an impact on prognosis (Klappacher et al., 1995; Kitahara et al., 2007; Zannad et al., 2000). In specific high collagen type I degradation levels were negatively associated with survival (Klappacher et al., 1995; Kitahara et al., 2007; Zannad et al., 2000). We hypothesized that the extent of collagen metabolism, as assessed by serum levels of a collagen type I degradation marker, would provide insight into the impact that ACE-inhibitor treatment has on survival in chronic heart failure patients. 2. Material and methods 2.1. Patients We prospectively studied 207 consecutive patients, who were admitted to the Coronary Care Unit, Department of Cardiology, with acute decompensation of chronic heart failure. The chronic heart failure status had been determined on a prior visit to our Outpatient Heart Failure Clinic. Patients were followed for up to 12 months after admission using a standardized protocol that included outpatient visits and telephone
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contacts. Follow up contacts were focused on the recording of ACEinhibitor treatment adherence. Patients who discontinued ACEinhibitor therapy (n = 6) were excluded. Furthermore, patients who failed to attend follow up visits (n = 3) or had incomplete follow up data (n = 2) were also excluded from further analysis. The remaining 196 patients (126 male, mean age 69 ± 10 years) constituted the study group. The endpoint of the study was cardiac death defined as death from worsening heart failure or sudden cardiac death.
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Chronic heart failure patients were divided into groups according to whether or not they received ACE-inhibitor therapy. Since treatment of study participants was in agreement with current published guidelines, restraining patients from ACE-inhibitor therapy was solely based on specific treatment contraindications/side-effects (Dickstein et al., 2008). Although chronic heart failure patients who were not on ACE-inhibitors fulfilled similar diagnostic criteria as chronic heart failure patients receiving such therapy (Table 1), they were more likely to have
Table 1 Comparison of baseline characteristics between angiotensin converting enzyme (ACE)-inhibitor treated and naive chronic heart failure patients. Variable
ACE-inhibitor naive patients n = 82
ACE-inhibitor treated patients n = 114
P
Age, years Male/Female, n Systolic blood pressure, mm Hg Heart rate, bpm QRS duration, s Body mass index (kg/m2)
68 (65–70) 52/30 120 (113–127) 84 (80–88) 0.11 (0.10–0.12) 29 (28–30)
68 (66–70) 74/40 146 (141–151) 74 (71–77) 0.10 (0.09–0.11) 30 (29–31)
0.812 0.880 b0.001a b0.001a 0.143 0.267
NYHA classification, n (%) II III IV
22 (27%) 42 (51%) 18 (22%)
42 (37%) 60 (53%) 12 (10%)
Etiology, n (%) Coronary artery disease Hypertensive cardiomyopathy Valve disease Idiopathic dilated cardiomyopathy
34 14 14 20
(42%) (17%) (17%) (24%)
50 (44%) 34 (30%) 16 (14%) 14 (12%)
Co-morbidities, n (%) Diabetes mellitus Hypertension Atrial fibrillation Smoking Respiratory disease
32 46 36 14 34
(39%) (56%) (44%) (17%) (41%)
52 (46%) 78 (68%) 54 (47%) 26 (23%) 38 (33%)
0.383 0.098 0.665 0.372 0.244
Echocardiographic findings Preserved systolic function, n (%) Left ventricular mass, g Left ventricular ejection fraction, %
12 (15%) 387 (360–414) 36 (34–39)
36 (32%) 412 (381–442) 42 (40–45)
0.007b 0.600 0.002a
Treatment during follow up, n (%) b-Blockers Diuretics Aldosterone antagonists Digitalis Nitrates Angiotensin receptor blockers Calcium channel blockers Amiodarone Statins Aspirin Clopidogrel Anticoagualants
12 82 26 32 44 20 16 12 26 34 16 30
26 (23%) 114 (100%) 38 (33%) 56 (49%) 58 (51%) 6 (5%) 30 (26%) 12 (11%) 48 (42%) 62 (54%) 12 (11%) 54 (48%)
Biochemical markers Hemoglobin, g/dl White blood count, x103/μl Creatinine, mg/dl Sodium, mg/dl Uric acid, mg/dl Albumin, g/dl Total cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 CRP, mg/dl CITP, ng/ml NT-proBNP, pg/ml
12.9 (12.6–13.3) 8.6 (8–9.2) 1.3 (1.2–1.4) 140 (139–142) 7.7 (7.3–8) 6.8 (6.7–6.9) 162 (150–173) 44 (41–46) 124 (108–139) 67 (61–72) 1.6 (1.3–2) 0.55 (0.44–0.66) 6327 (4100–8554)
0.062
0.056
(15%) (100%) (32%) (40%) (54%) (24%) (20%) (15%) (32%) (42%) (20%) (37%)
13.3 (13–13.6) 8.7 (8.3–9.2) 1.2 (1.2–1.3) 142 (141–142) 7.6 (7.3–7.9) 6.7 (6.6–6.8) 173 (164–182) 45 (43–48) 142 (114–170) 69 (64–73) 1.6 (1.3–2) 0.43 (0.37–0.49) 2723 (2141–3306)
0.200 1.000 0.878 0.242 0.772 b0.001b 0.308 0.388 0.179 0.083 0.098 0.145
0.084 0.746 0.314 0.059 0.808 0.543 0.120 0.480 0.311 0.591 0.460 0.034a 0.003a
Values are expressed as means and 95% CI for continuous variables and as number of patients and % for categorical variables. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I, CRP; C-reactive protein, HDL; high density lipoprotein, NTproBNP; N-terminal propeptide of brain natriuretic peptide, and NYHA; New York Heart Association. a For unpaired Student's t-test. b For chi-square test.
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contraindications for ACE-inhibitor use, i.e. hypotension, history of drug related-cough, and history of angioedema (Dickstein et al., 2008). Peripheral blood samples were obtained from all patients at discharge after resolution of symptoms and restoration of a clinical stable status. The compensated chronic heart failure status was documented by the absence of dyspnoea at rest, orthopnoea and body weight close to their known dry body weight, the absence of pulmonary rales, third heart sound, and leg oedema on clinical examination and the absence of pulmonary venous congestion on chest radiography. Furthermore, after resolution of symptoms an echocardiography study was performed using standard techniques (Cheitlin et al., 1997), in which left ventricular ejection fraction and left ventricular mass were assessed (Feigenbaum et al., 2005). Exclusion criteria were (1) acute decompensation of chronic heart failure due to acute medical illness, acute coronary syndrome, severe aortic stenosis, hypertrophic cardiomyopathy and excessive alcohol intake and (2) renal insufficiency (plasma creatinine N 2 mg/dl), liver, autoimmune, thyroid, bone, haematological, lung, neoplastic disease and major trauma or surgery in the last 3 months. All subjects gave written informed consent, and were studied in compliance with ethical approval and were on standard medical treatment for heart failure.
2.2. Biochemistry analysis Samples were drawn from a peripheral vein of the patients and after centrifugation at 4000 rpm for 10 min, serum samples were frozen and stored at −70 °C until use. Serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) were measured by commercially available immunoassays (ELECSYS 1010, Roche Diagnostics Ltd, Switzerland). Minimum detectable concentration of CITP was b0.01 ng/ml with intra-assay and inter-assay of 4.6% and 4.7% respectively.
3. Results Table 2 summarizes the baseline characteristics of study participants. There were 56 cardiac deaths during follow up. The mean observation period for survival was 322 ± 90 days. Cumulative event-
Table 2 Baseline characteristics of study population. Variable
All study participants n = 196
Age, years Male/Female, n Systolic blood pressure, mm Hg Heart rate, bpm QRS duration, sec Body mass index (kg/m2)
68 (66–69) 126/70 139 (135–143) 78 (76–81) 0.11 (0.10–0.11) 30 (29–30)
NYHA classification, n (%) II III IV
64 (33%) 102 (52%) 30 (15%)
Etiology, n (%) Coronary artery disease Hypertensive cardiomyopathy Valve disease Idiopathic dilated cardiomyopathy
84 48 30 34
Co-morbidities, n (%) Diabetes mellitus Hypertension Atrial fibrillation Smoking Respiratory disease
84 (43%) 124 (63%) 90 (46%) 40 (20%) 72 (37%)
Echocardiographic findings Preserved systolic function, n (%) Left ventricular mass, g Left ventricular ejection fraction, %
48 (25%) 401 (380–422) 40 (38–42)
Treatment, n (%) ACE-inhibitors b-Blockers Diuretics Aldosterone antagonists Digitalis Nitrates Angiotensin receptor blockers Calcium channel blockers Amiodarone Statins Aspirin Clopidogrel Anticoagualants
Pre study entry 124 (63%) 46 (24%) 164 (84%) 44 (22%) 76 (39%) 70 (36%) 26 (13%) 44 (22%) 8 (4%) 56 (29%) 86 (44%) 30 (15%) 50 (26%)
Biochemical markers Hemoglobin, g/dl White blood count, x103/μl Creatinine, mg/dl Sodium, mg/dl Uric acid, mg/dl Albumin, g/dl Total cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 CRP, mg/dl CITP, ng/ml NT-proBNP, pg/ml
13.2 (12.9–13.4) 8.7 (8.3–9) 1.2 (1.2–1.3) 141 (140–142) 7.6 (7.4–7.9) 6.8 (6.7–6.8) 168 (161–175) 44 (43–46) 134 (117–152) 68 (64–71) 1.6 (1.4–1.9) 0.48 (0.42–0.54) 4231 (3220–5243)
(43%) (25%) (15%) (17%)
2.3. Statistical analysis Statistical analyses were performed with SPSS 15 (SPSS Inc., Chicago, Illinois). Statistical analyses consisted of an evaluation of baseline serum CITP levels as predictors of survival, and testing the relationship between baseline CITP levels and survival benefit from ACE-inhibitor use. Association between CITP levels and survival was analyzed by using marker values as a categorical variable with a cutoff value the median of its distribution. Results are presented as means with 95% confidence intervals (CI) for continuous variables and as percentages for categorical data. Normality was tested using Kolmogorov–Smirnov test. Creatinine, sodium, total-, high density lipoprotein- (HDL-) cholesterol, C-reactive protein (CRP), triglycerides, CITP and N-terminal propeptide of brain natriuretic peptide (NT-proBNP) levels as well as QRS duration and left ventricular mass were not normally distributed and were therefore logarithmically transformed as required to approach normal distribution and to obtain equal variances. Comparisons between categorical variables were performed by a chi-square test or Fisher's exact test when required. Differences in continuous variables between two groups were assessed using the unpaired Student's t-test. Univariate and multivariate Cox proportional hazard analyses were performed to determine independent predictors of the study endpoint. Adjusted hazard ratios were assessed in multivariate Cox models using as cofounders variables that on a univariate analysis were shown to be different between under study groups (low CITP vs. high CITP or ACEinhibitors users vs. ACE-inhibitor naive patients). Time-to-event distributions were summarized with Kaplan–Meier curves and compared by the log-rank test. A P valueb 0.05 was considered statistically significant.
During follow up 114 (58%) 38 (19%) 196 (100%) 64 (33%) 88 (45%) 102 (52%) 26 (13%) 46 (24%) 24 (12%) 74 (38%) 96 (49%) 28 (14%) 84 (43%)
Values are expressed as means and 95% CI for continuous variables and as number of patients and % for categorical variables. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I, CRP; C-reactive protein, HDL; high density lipoprotein, NT-proBNP; N-terminal propeptide of brain natriuretic peptide, and NYHA; New York Heart Association.
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free survival rate was 98% at 1 month, 90% at 3 months, 87% at 6 months, 83% at 9 months and 71% at 12 months. Baseline CITP, with a cut-off value of 0.38 ng/ml (median value) was significantly (P = 0.002) and negatively correlated with survival in the whole study population since patients with high CITP levels (N0.38 ng/ml) had a survival rate of 62% compared to patients with low CITP levels (≤0.38 ng/ml) who had a survival rate of 81.2% (Fig. 1). A univariate Cox proportional hazard analysis showed that patients with high CITP levels had a hazard ratio of 2.3 (95% CI 1.3–4, P = 0.004) compared to patients with low CITP levels. In a multivariate Cox model (with cofounders the variables that were different between the two groups, Table 3) patients with high CITP levels had an adjusted hazard ratio of 2 (95% CI 1.1–3.8, P = 0.026) compared to patients with low CITP levels. The study population was then divided in 4 groups based on a CITP median value (0.38 ng/ml) as well as on being under therapy with ACE-inhibitors or not (Group A (n = 36): not on ACE-inhibitors/low CITP levels, Group B (n = 60): on ACE-inhibitors/low CITP levels, Group C (n = 54): on ACE-inhibitors/high CITP levels, and Group D (n = 46): not on ACE-inhibitors/high CITP levels). A Kaplan–Meier survival curve analysis showed that event-free rates were significantly lower in Group D compared to other subgroups (overall P b 0.001, Fig. 2). Specific patients in Group D had a lower survival rate (52.2%) compared to patients of Group A (survival rate 83.3%, P = 0.003), of Group B (survival rate 80%, P = 0.006) and of Group C (survival rate 70.4%, P = 0.015). In contrast, survival rates did not differ between Group A and Group B (P = 0.748) or Group C (P = 0.217). Similarly, survival rates were not significantly different between Groups B and C (P = 0.283). The increased cardiac risk of patients in Group D was preserved in a multivariate Cox proportional hazard model (Table 4). Furthermore, among the subgroup not under ACE-inhibitor therapy (n = 82), patients with high CITP levels (N0.38 ng/ml) compared to patients with low CITP levels (≤0.38 ng/ml) had an adjusted hazard ratio of 2.71 (95% CI 1.17–8.79, P = 0.037). Specifically, patients with high CITP levels had a significantly lower (P = 0.026) survival rate of 52.2% compared to patients with low CITP levels (survival rate of 83.3%) (Fig. 3). In contrast, among the subgroup under ACE-inhibitor therapy (n = 114), baseline CITP levels were not associated with survival (P = 0.604) since patients with high CITP levels had a similar (P = 0.283) survival rate (80%) compared to patients with CITP levels (survival rate of 70.4%). Conversely, among the subgroup with CITP levels above median (N0.38 ng/ml) (n = 100), use of ACE-inhibitors was associated with a survival benefit (adjusted hazard ratio of 0.51 95% CI 0.24–0.07,
Table 3 Comparison of baseline characteristics between patients with high (N0.38 ng/ml) and low carboxy-terminal telopeptide of collagen type I (CITP) (≤ 0.38 ng/ml) levels. Variable
Low CITP levels (n = 96)
High CITP (n= 100)
Age, years Male/Female, n Systolic blood pressure, mm Hg Heart rate, bpm QRS duration, s Body mass index (kg/m2)
67 (65–69) 70/26 142 (137–147)
68 (66–70) 56/44 137 (130–144)
0.389 0.017a 0.260
75 (72–79) 0.11 (0.09–0.11) 31 (30–32)
81 (77–84) 0.11 (0.10–0.12) 28 (27–29)
0.029b 0.358 0.001b
NYHA classification, n (%) II III IV
32 (33%) 52 (54%) 12 (13%)
32 (32%) 50 (50%) 18 (18%)
48 18 12 18
(50%) (19%) (13%) (19%)
36 30 18 16
(36%) (30%) (18%) (16%)
42 56 42 30 35
(44%) (58%) (44%) (31%) (36%)
42 68 48 10 37
(42%) (68%) (48%) (10%) (37%)
Etiology, n (%) Coronary artery disease Hypertensive cardiomyopathy Valve disease Idiopathic dilated cardiomyopathy Co-morbidities, n (%) Diabetes mellitus Hypertension Atrial fibrillation Smoking Respiratory disease Echocardiographic findings Preserved systolic function, n (%) Left ventricular mass, g Left ventricular ejection fraction, %
P
0.560
0.114
0.885 0.183 0.569 b0.001a 0.937
22 (23%)
26 (26%)
0.623
388 (357–419)
414 (385–443)
0.128
39 (37–42)
40 (38–43)
0.640
54 (54%) 16 (16%) 100 (100%) 38 (38%) 42 (43%) 54 (54%) 8 (8%) 30 (30%) 16 (16%) 32 (32%) 42 (42%) 20 (20%) 36 (36%)
0.249 0.279 1.000 0.128 0.564 0.668 0.035a 0.030a 0.128 0.106 0.063 0.024a 0.060
Treatment during follow up, n (%) ACE-inhibitors 60 (63%) b-Blockers 22 (23%) Diuretics 96 (100%) Aldosterone antagonists 26 (27%) Digitalis 46 (48%) Nitrates 48 (50%) Angiotensin receptor blockers 18 (19%) Calcium channel blockers 16 (17%) Amiodarone 8 (8%) Statins 42 (44%) Aspirin 54 (56%) Clopidogrel 8 (8%) Anticoagualants 48 (50%) Biochemical markers Hemoglobin, g/dl White blood count, x103/μl Creatinine, mg/dl Sodium, mg/dl Uric acid, mg/dl Albumin, g/dl Total cholesterol, mg/dl HDL cholesterol, mg/dl Triglycerides, mg/dl Glomerular filtration rate, ml/min/1.73 m2 CRP, mg/dl NT-proBNP, pg/ml
Fig. 1. A Kaplan–Meier analysis of cardiac event-free rates among whole study population (n = 196) stratified into subgroups based on carboxy-terminal telopeptide of collagen type I (CITP) levels. Low CITP levels (≤0.38 ng/ml): black line. High CITP levels (N 0.38 ng/ml): grey line. CITP; carboxy-terminal telopeptide of collagen type I.
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13.3 (13–13.6) 8.8 (8.3–9.4) 1.2 (1.2–1.3) 141 (141–142) 7.6 (7.3–8) 6.8 (6.7–6.9) 178 (168–188) 46 (44–49) 157 (123–192) 74.2 (68.9–79.5)
13 (12.7–13.3) 8.6 (8.1–9.1) 1.3 (1.2–1.3) 141 (140–142) 7.6 (7.3–7.9) 6.7 (6.6–6.9) 159 (149–168) 43 (40–45) 112 (103–121) 61.8 (57.4–66.2)
1.4 (1.2–1.6) 1.9 (1.5–2.3) 3399 (2261–4538) 5030 (3370–6689)
0.174 0.462 0.313 0.642 0.906 0.728 0.005b 0.069 0.004b b0.001b 0.133 0.183
Values are expressed as means and 95% CI for continuous variables and as number of patients and % for categorical variables. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I, CRP; C-reactive protein, HDL; high density lipoprotein, NT-proBNP; N-terminal propeptide of brain natriuretic peptide, and NYHA; New York Heart Association. a For chi-square test. b For unpaired Student's t-test.
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Fig. 2. A Kaplan–Meier analysis of cardiac event-free rates among chronic heart failure patients stratified into subgroups based on carboxy-terminal telopeptide of collagen type I (CITP) levels and angiotensin converting enzyme (ACE)-inhibitor therapy. Group A (n = 36): ACE-inhibitors (−)/low CITP levels (≤ 0.38 ng/ml), (solid black line, ). Group B (n = 60): ACE-inhibitors (+)/low CITP levels (≤0.38 ng/ml), (dotted black line, ). Group C (n = 54): ACE-inhibitors (+)/high CITP levels (N0.38 ng/ml), (dotted grey line, ). Group D (n = 46): ACE-inhibitors (−)/ high CITP levels (N0.38 ng/ml), (solid grey line, ). ACE; angiotensin converting enzyme, CITP; and carboxy-terminal telopeptide of collagen type I.
P = 0.041) while in the subgroup with CITP levels below median (≤0.38 ng/ml) (n = 96) there was no survival benefit (adjusted hazard ratio of 0.59 95% CI 0.19–1.82, P = 0.360) (Fig. 4). 4. Discussion The present study is among the first to demonstrate that serum levels of collagen metabolism may correlate with the level of impact that ACE-inhibitor therapy has on survival in chronic heart failure patients. The main findings of the present study may be summarized as follows: i) chronic heart failure patients with high serum levels of CITP were characterized by worse survival compared to patients with low levels, and ii) the ACE-inhibitor related improvement in mortality was most predominant in chronic heart failure patients with high CITP levels. Findings of our study may be of clinical relevance since a novel approach of tailoring ACE-inhibitor therapy is implied. Not all patients respond to ACE-inhibitors equally (Dickerson et al., 1999; Struthers et al., 2001). Moreover, several subgroup analyses of large ACE-inhibitor trials have shown that the beneficial treatment effect of ACE-inhibitors is consistent among subgroups of specific clinical characteristics and also is independent of baseline risk (Kazi
Fig. 3. A Kaplan–Meier analysis of cardiac event-free rates among angiotensin converting enzyme-inhibitor naive patients (n = 82) stratified into subgroups based on carboxyterminal telopeptide of collagen type I (CITP) levels. Low CITP levels (≤0.38 ng/ml): black line. High CITP levels (N 0.38 ng/ml): grey line. CITP; carboxy-terminal telopeptide of collagen type I.
and Deswal, 2008; Shekelle et al., 2003). In addition, in the secondary prevention setting, there are no means by which we can guide or tailor ACE-inhibitor therapy. A hypothesis has been raised according to which the observed differences in treatment benefit may lay on the differential activation status of the renin–angiotensin–aldosterone system (RAAS) (Hoite, 2003). Increasing evidence strongly supports the notion that angiotensin II influences both fibrillar collagen synthesis and degradation through direct effects on cardiac fibroblasts. Different signalling pathways of the angiotensin type-1 receptor (AT1R) may modulate collagen synthesis such as the MAP/ERK kinase pathway and TGF-b1 signalling pathways (Gonzalez et al., 2002). In addition to collagen synthesis, angiotensin II stimulation of the AT1R has been shown to
Table 4 Multivariate Cox proportional hazard analysis for predicting cardiac events in whole study group.
Group A Group B Group C
Hazard ratio
95% CI
P value
0.36 0.38 0.53
0.14–0.92 0.18–0.82 0.26–0.96
0.035 (overall) 0.033 0.013 0.039
Hazard ratios refer to comparisons with Group D (reference group). Group A (n = 36): ACE-inhibitors (−)/low CITP levels (≤0.38 ng/ml). Group B (n = 60): ACE-inhibitors (+)/low CITP levels (≤0.38 ng/ml). Group C (n = 54): ACE-inhibitors (+)/high CITP levels (N 0.38 ng/ml). Group D (n = 46): ACE-inhibitors (−)/high CITP levels (N 0.38 ng/ml). Systolic blood pressure, heart rate, ejection fraction, angiotensin receptor blockers use, presence of preserved systolic function and NT-proBNP levels (high vs. low) appeared as covariates in the model. ACE; angiotensin converting enzyme, CI; confidence intervals, CITP; carboxy-terminal telopeptide of collagen type I.
Fig. 4. Adjusted hazard ratios associated with angiotensin converting enzyme-inhibitor (ACE-i) use according to baseline carboxy-terminal telopeptide of collagen type I (CITP) levels. Horizontal lines indicate 95% confidence intervals. CITP median levels = 0.38 ng/ ml. Systolic blood pressure, heart rate, ejection fraction, angiotensin receptor blockers use, presence of preserved systolic function and NT-proBNP levels (high vs. low) appeared as covariates in the model. ACE-i; angiotensin converting enzyme inhibitors, CITP; carboxy-terminal telopeptide of collagen type I, NT-proBNP; and N-terminal propeptide of brain natriuretic peptide.
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regulate collagen degradation by attenuating matrix metalloproteinase (MMP) activity and by enhancing tissue inhibitor (TIMP) production (Gonzalez et al., 2002). Angiotensin II also increases aldosterone secretion, which is known to participate in cardiac fibrosis via enhancing collagen synthesis and deposition through mineralocorticoid receptors (Zannad et al., 2001). Therefore, chronic heart failure patients with increased activation of RAAS are characterized by an excessively altered collagen metabolism and those patients could be associated with a broader clinical benefit with the use of ACE-inhibitors. On the basis of a number of clinical and experimental observations, it has been suggested that the serum concentration of CITP reflects the rate of extracellular degradation of collagen type I (Yamamoto et al., 2002). Myocardial fibrosis has been shown to be accompanied by collagen degradation and MMP activation, suggesting that collagen degradation is a prerequisite for collagen synthesis, accumulation and fibrosis (Jugdutt, 2003). Additionally, myocardial fibrosis seen with chronic heart failure is characterized also with a shift of collagen phenotype from type I to type III (Yamamoto et al., 2002; Jugdutt, 2003). It is possible that degradation of collagen type I associated with the aforementioned collagen phenotype shift to represent a first step of ventricular fibrosis. Therefore, it is logical to hypothesize that increased CITP levels may reflect excessive collagen synthesis and also an activated status of the RAAS. Several studies have addressed the role of molecule degradation of collagen type I (CITP) in heart failure. In agreement to our study, Klappacher et al., have shown the negative prognostic value of high CITP levels in patients with idiopathic or ischemic dilated cardiomyopathy (Klappacher et al., 1995). Kitahara et al., have shown that high CITP levels are associated with adverse cardiac events in chronic heart failure patients with preserved left ventricular systolic function (Kitahara et al., 2007). Findings from our study should be viewed with certain limitations in mind. We assessed the circulating levels of CITP, instead of the more accurate myocardial levels of CITP. Myocardial biopsies however are difficult to perform in vivo and also unethical to perform since it would not contribute to patient care. Additionally, the use of bblockers, angiotensin receptor blockers and aldosterone antagonists may influence serum levels of CITP, since it has been shown that their use is capable of modulating collagen metabolism (Jugdutt, 2003). The use of multivariate regression models, however could account for possible confounders. Not all of our study participants were optimally treated for heart failure. Specifically, ACE-inhibitors (approximate prescription rate of 60%), b-blockers (approximate prescription rate of 20%) and aldosterone antagonists (approximate prescription rate of 30%) were underutilized in our study population, in agreement though with rates reported in large survey trials (Komajda et al., 2003; Cleland et al., 2002). Specifically, the low prescription rates for b-blockers may be attributed to the relatively old age, the high female to male ratio as well as the high prevalence of respiratory disease of our study population (Follath, 2006). Under the same notion, the relatively old age as well as the high prevalence of mild renal disease in our study population may account for the low prescription rates of aldosterone antagonists (Komajda et al., 2003; Cleland et al., 2002). Similarly, old age, high prevalence of mild renal dysfunction and low blood pressure may account for the low usage of angiotensin receptor blockers in ACE-inhibitor intolerant patients. Furthermore, the high rate of nitrate use in our study population, although in keeping with that reported in the EuroHeart Failure Programme (Komajda et al., 2003) may be attributed to the fact that ischemic heart disease—where nitrates are used more often—was common among study participants. It would be of interest to assess if the aforementioned benefit of ACE-inhibitors is still present in optimally treated patients with high CITP levels; however our study was not powered enough to yield significant results in this study subgroup.
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Finally, ACE-inhibitor treatment allocation (treated or not) was based on the presence or not of side-effects/contraindications and not performed in a randomized manner. Although our study was powered enough to detect differences in survival rates between study subgroups, multi-group comparisons and the associated hyper-inflation error may have influence our results. Therefore, extrapolation of the results of this study should be done cautiously. Ιn conclusion, serum collagen type I turnover markers are of predictive value in chronic heart failure patients and specifically high CITP levels are associated with poor survival rates. Furthermore, CITP levels possibly reflecting an activated status of the RAAS, may be of clinical relevance since they identify a subgroup of patients that is more susceptible to treatment with an ACE-inhibitor.
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