European Heart Journal Advance Access originally published online on March 10, 2008
European Heart Journal 2008 29(7):898-906; doi:10.1093/eurheartj/ehn098
Impact of collagen type I turnover on the long-term response to cardiac resynchronization therapy
1 Department of Cardiology and Cardiovascular Surgery, University Clinic, School of Medicine, University of Navarra, Pamplona, Spain
2 Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain
Received 20 April 2007; revised 16 January 2008; accepted 14 February 2008; online publish-ahead-of-print 10 March 2008.
* Corresponding author: Area de Ciencias Cardiovasculares, Edificio CIMA, C/ Pío XII, 55, 31008 Pamplona, Spain. Tel: +34 948 194700, Fax: +34 948 194716, Email: jadimar{at}unav.es
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Abstract |
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Aims: We investigated whether collagen type I turnover influences the long-term response to cardiac resynchronization therapy (CRT).
Methods and results: Serum carboxy-terminal propeptide of procollagen type I or PICP (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I or CITP (a marker of collagen type I degradation) were measured in heart failure patients at baseline and after 1 year of CRT. Patients were categorized as responders or non-responders if they increased the distance walked in 6 min by > or <10%, respectively. At baseline, the PICP:CITP ratio, an index of the degree of coupling between collagen type I synthesis and degradation was higher (P = 0.006) in responders than in non-responders. Whereas the PICP:CITP ratio decreased (P= 0.000) after treatment in responders, it remained unchanged in non-responders. Thus, at 1-year, the PICP:CITP ratio was similar in the two groups of patients. A direct correlation (r = 0.289, P = 0.037) was found between the baseline PICP:CITP ratio and the change in the distance walked in 6 min in all patients. Receiver operating characteristics curves showed that a cut-off value of 14.4 for the PICP:CITP ratio provided 70% specificity and 63% sensitivity for the predicting response to CRT with a relative risk of 2.07 (95% confidence interval, 0.98–4.39).
Conclusion: Collagen type I turnover influences the long-term response to CRT. In addition, the ability of CRT to restore the balance between collagen type I synthesis and degradation is associated with a beneficial response.
Key Words: Collagen • Heart failure • Resynchronization
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Introduction |
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Cardiac resynchronization therapy (CRT) via atrial-synchronous biventricular pacing has emerged as an effective treatment for refractory congestive heart failure (HF) patients with ventricular dyssynchrony.1 Although randomized, controlled trials have demonstrated that CRT significantly improves functional clinical status, ventricular remodelling, and survival, approximately 30% of patients do not respond to this therapy.2–4 Asynchronous ventricular activation causes left ventricular (LV) dilatation and reduction in ejection fraction (EF) and redistribution of myocardial blood flow via several pathways, including changes in myocardial tissue composition.5–8 Fibrous tissue accumulation is an integral feature of the adverse structural changes of cardiac tissue. Findings from clinical studies suggest that histologically proven myocardial fibrosis is related with LV dilatation and depression of EF,9,10 ventricular arrhythmias,11 and alterations of myocardial blood flow leading to reduced coronary flow reserve.12
Some of the beneficial effects of CRT are probably linked to its ability to induce regression of severe myocardial fibrosis. In fact, CRT has been shown to induce a significant reduction of myocardial collagen fibres13 and, in responder patients, to normalize the serum levels of the carboxy-terminal propeptide of procollagen type I (PICP),14 a 100 kDa peptide cleaved from procollagen type I during the synthesis of fibril-forming collagen type I that is associated with the extent of myocardial deposition of collagen type I fibrils in HF patients.10 Thus, a limitation of the excessive cardiac synthesis and deposition of collagen type I fibrils may be one of the mechanisms contributing to the clinical effects of CRT. However, since myocardial fibrosis is the result of both increased collagen synthesis by fibroblasts and unchanged or decreased extracellular fibrillar collagen degradation,15 the potential effect of CRT on extracellular collagen type I degradation by matrix metalloproteinases (MMPs), namely MMP-1, -2, and -9, must be also considered.
Serum concentrations of the carboxy-terminal telopeptide of collagen type I (CITP), a 12 kDa peptide produced when collagen type I fibrils undergo hydrolysis, have been widely used as an index of extracellular collagen type I degradation by MMP-1.16 Recent data indicate that circulating MMP-1 and its tissue inhibitor (TIMP)-1 detected in HF patients may be of cardiac origin and that the ratio MMP-1:TIMP-1 may be useful as an index of the MMP-1/TIMP-1 system within the myocardium.17
We have hypothesized that collagen type I turnover (the balance between synthesis and degradation) may play a role in the long-term response to CRT in patients with HF and LV dyssynchrony. To test this hypothesis, the ratio of the serum concentration of PICP to the serum concentration of CITP, as well as serum concentrations of MMP-1, -2, and -9, and TIMP-1 were prospectively measured in HF patients before and after 1 year of CRT.
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Study design and subjects
All subjects gave written informed consent to participate in the study, and the local committee on human research approved the study protocol. The study conformed with the principles of the Declaration of Helsinki.
Between June 2003 and July 2005, 73 consecutive patients scheduled for CRT with HF in New York Heart Association (NYHA) functional class III or IV despite optimal pharmacologic therapy, LV EF <35%, and left bundle branch block with a QRS duration >130 ms were screened for this study. Individuals with atrial fibrillation or an indication for implantation of a cardioverter-defibrillator were also included in the study. In patients with permanent atrial fibrillation, biventricular pacing was ensured with radiofrequency ablation of the AV junction or drug therapy to obtain permanent (>80%) biventricular pacing. Seven patients with conditions associated with alterations in serum concentrations of PICP, CITP, MMPs, or TIMP-1 were excluded. Within the remaining 66 patients, 5 refused participation in the study, while 61 gave both oral and written informed consent. Six of these 61 patients initially enrolled in the study died during follow-up. These patients died as follows: two patients with non-ischaemic cardiomyopathy died suddenly 4 and 7 months after the implant. During this period, they did not required hospitalizations for HF. Three patients died of progressive HF and one died of genitourinary sepsis. One year after CRT, one additional patient was not able to exercise due to an ischaemic stroke.
Patients were evaluated at baseline (pre-implant) and at the 1-year follow-up visit. Evaluation included NYHA functional class, quality-of-life evaluation (with the use of the Minnesota Living with Heart Failure Questionnaire), and a standardized 6 min walk test according to the American Thoracic Society recommendations,18 echocardiographic study, and obtaining blood samples for biochemical determinations. At 1 year, patients were categorized as responders if they increased the distance walked in 6 min by >10%19 and as non-responders if they did not increase the distance walked in 6 min or died due to a cardiac cause before the 12-month follow-up.
In the population sample of a previous study14 beside serum PICP, we also measured serum CITP to assess the PICP:CITP ratio. With the obtained PICP:CITP ratio values and considering an 
error of 0.05 and a ß error of 0.20, we calculated that the minimal sample size necessary to observe statistical differences between responders and non-responders was of 19 patients in each group.
Device implantation
Implantation was performed in an electrophysiology laboratory. All patients underwent angiography of the coronary venous system, and the over-the-wire LV lead was implanted preferably in the lateral region. An anterior site was chosen as a last resort if lateral implantation was not possible or if a lateral site produced unacceptable pacing thresholds or phrenic nerve stimulation. The anterior zone was defined as lying between 11 and 2 O' clock and the lateral zone as lying between 2 and 5 O' clock in the 45° left anterior oblique projection.
The atrioventricular and interventricular delays were optimized at rest by echo-Doppler. A proper biventricular stimulation was checked at discharge, at a 3-month intermediate follow-up, and at the 1-year follow-up by measurement of thresholds and radioscopic control of the leads.
Echocardiographic evaluation
Transthoracic two-dimensional echocardiograms, M-mode recordings, and Doppler ultrasound measurements were performed in each patient at baseline and 1 year thereafter using a Sonos 5500 ultrasound system (Phillips). All echocardiographic studies were performed by a cardiologist who was blinded to the patient's clinical status. Images were taken in the parasternal long- and short-axis views, six chamber apical views, and subxiphoid view. LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) were measured from M-mode recordings using leading edge methodology according to the American Society of Echocardiography criteria.20 The EF was determined with the Simpson method.
Intraventricular dyssynchrony was measured with the septal-to-lateral-wall motion delay (SLWMD) assessed by tissue echo-Doppler as the difference (in milliseconds) between the onset of the QRS complex and the maximum systolic velocity of each ventricular region along the four-chamber apical axis. The final value was the mean of three measurements of different cycles. The Tei index, a Doppler-derived index that reflects both systolic and diastolic function, which has been previously used to assess the LV performance in CRT,21 was calculated by assessing isovolumic contraction time and isovolumic relaxation time divided by ejection time.22 The degree of mitral regurgitation was assessed semi-quantitatively with colour Doppler.
Blood sampling and biochemical determinations
Blood samples were withdrawn from the left antecubital vein at the time of the clinical studies and stored at –40°C. Serum PICP and CITP were determined by specific enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay methods, respectively, as previously reported.14,23 The PICP:CITP ratio was considered as an index of the degree of coupling between the synthesis and degradation of collagen type I, respectively. Free MMP-1 and TIMP-1 were determined in serum by ELISA methods as previously reported.23 The MMP-1-to-TIMP-1 ratio was used as an index of the balance between MMP-1 and the inhibitor. MMP-2 and -9 were measured by sandwich ELISA (inter-assay and intra-assay variations were 9.8% and 5.6% for MMP-2, and 8.8% and 5.2% for MMP-9). Amino-terminal pro-brain natriuretic peptide (NT-proBNP) was measured in serum samples by ELISA. The sensitivity was 5 pg of NT-proBNP/ml. The inter-assay and intra-assay coefficients of variation were lower than 2%.
Statistical analysis
Differences at baseline and after 1 year of CRT between responders and non-responders were tested by Student's t-test for unpaired data once normality was demonstrated (Shapiro–Wilks test); otherwise, a non-parametric test (Mann–Whitney U test) was used. Differences in parameters before and after treatment within each group of patients were tested by the Student's t-test for paired data once normality was demonstrated (Shapiro–Wilks test); otherwise, a non-parametric test (Wilcoxon test) was used. Correlations were estimated by univariate regression analysis using Pearson correlation coefficient once normality was demonstrated (Shapiro–Wilks test); otherwise, Spearman correlation coefficient was used. Values are expressed as mean ± standard deviation (SD). A value of P < 0.05 was considered statistically significant for two-sided tests. Receiver operating characteristic (ROC) curves allowed determination of the overall performance of the PICP:CITP ratio, NT-proBNP and LVEDD for predicting response to CRT in the whole population of patients. The chosen cut-off value for all the above three parameters was that presenting the maximum sum of sensitivity and specificity. The analysis of the ROC curves was performed with the program Analyse-it, version 2.05. All statistical tests were performed with the SPSS 15.0 statistical package (SPSS Inc., Chicago, IL, USA).
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Classification of patients and baseline characteristics
At the end of follow-up, 35 patients (62%) were considered responders to CRT according to the previously defined criteria. There were 24 non-responders (38%), of whom 15 did not increase the distance walked in 6 min by >10%, 4 were submitted to heart transplantation at the end of the follow-up, and 5 died of a cardiac cause during the study.
Baseline clinical and echocardiographic characteristics of the patients in each group are presented in Table 1. Most patients in the two groups were treated with the combination of a loop diuretic, a β-blocker, and either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor antagonist. No differences were found between the two groups in the distribution of the different classes of pharmacological compounds.
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As shown in Table 2, the PICP:CITP ratio was higher in responders than in non-responders. Whereas serum concentration of PICP was higher in responders than in non-responders, serum concentrations of CITP, MMP-1, TIMP-1, MMP-2, and MMP-9 and the ratio MMP-1:TIMP-1 were similar in the two groups of patients (Table 2).
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Effects of cardiac resynchronization therapy in patients who completed the follow-up
As shown in Table 3, the distance walked in 6 min after 1 year of CRT was higher in responders that finished the study (N = 35) than in non-responders that did not finish the study (N = 19). Responders increase this distance by a mean of 139 ± 97 m (57 ± 18%) whereas non-responders increased by a mean of 13 ± 32 m (2 ± 8%), this difference being significant (P = 0.000). Mean NYHA class and quality of life improved at 1 year in responders but were unchanged in the non-responders (Table 3). As a consequence, final values of these two parameters were significantly different in responders than in non-responders.
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Whereas LV diameters and EF decreased and increased, respectively, in responders, they did not change in non-responders (Table 3). Thus, the final values of LV diameters and EF were lower and higher, respectively, in responders than in non-responders. Whereas the Tei index and SLWMD decreased in responders, they remained unchanged in non-responders (Table 3). In accordance with this, the final values of these parameters were significantly different in the two groups of patients. Although NT-proBNP decreased in responders and remained unchanged in non-responders, no significant differences were found in the final values of this parameter between the two groups of patients (Table 3).
As shown in Table 4, the PICP:CITP ratio decreased in responders and remained unchanged in non-responders. Thus, after 1 year of CRT, the final values of the ratio were similar in the two groups of patients. PICP decreased and increased in responders and non-responders, respectively. After 1 year of CRT, PICP was lower in responders than in non-responders. No changes in CITP were observed after CRT in the two groups of subjects. Thus, final values of CITP were similar in responders and non-responders.
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Whereas in the responder group, MMP-1 and the MMP-1:TIMP-1 ratio increased and TIMP-1 decreased after 1 year of CRT; no changes in these parameters were found in non-responders (Table 4). Nevertheless, no differences in the final values of MMP-1, TIMP-1, and the MMP-1:TIMP-1 ratio were observed between the two groups of patients. MMP-9 increased in responders and did not change in non-responders after 1 year of CRT. MMP-2 did not change in either group of patients (Table 4). No differences were observed in the final values of these two MMPs between the two groups of patients.
Analysis of associations
A direct correlation (r = 0.289, P = 0.037) was found between the baseline PICP:CITP ratio and the change in the distance walked in 6 min, as assessed by the formula [(final distance–baseline distance):baseline distance x 100] in all patients (Figure 1), suggesting that baseline collagen type I turnover was actually related to the clinical response of patients to CRT. The correlations between final values of the PICP:CITP ratio and the final values of clinical and echocardiographic parameters assessing the response to CRT were analysed in responders. As shown in Figure 2, the PICP:CITP ratio was inversely correlated with EF (r = –0.501, P = 0.002), and directly correlated with LVEDD (r = 0.376, P = 0.026). No correlations were found between the PICP:CITP ratio and the distance walked in 6 min, LVESD, and Tei index.
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Analysis of receiver operating characteristic curves
The ROC curves show the overall performance of the PICP:CITP ratio, NT-proBNP, and LVEDD for predicting response to CRT (Figure 3). The area under the ROC curve was larger (P = 0.020) for the PICP:CITP ratio than for NT-proBNP and LVEDD. Only the area under the ROC curve for the PCIP:CITP ratio was higher (P = 0.000) than 0.50. From the ROC curves, cut-off values of reference for the PICP:CITP ratio, NT-proBNP, and LVEDD were calculated. The sensitivity and specificity of each of these three values for predicting response to CRT are presented in Table 5. Overall, the cut-off value of the PICP:CITP ratio showed better sensitivity and specificity. Thus, the odds ratio of presenting a favourable response to CRT was higher for patients with PICP:CITP ratio values >14.4 than for patients with NT-proBNP values >1332 pg/mL or patients with LVEDD values >67.5 mm.
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Discussion |
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The major finding of the present study is that the PICP:CITP ratio is associated with the response to CRT in HF patients. More specifically, we found that an enhanced baseline PICP:CITP ratio, as a consequence of an excess of PICP, predicts the long-term response to CRT in HF patients. In addition, we reported that the reduction of the PICP:CITP ratio, as a result of the decrease in PICP, is associated with a positive response to CRT in these patients. Collectively these findings suggest that an altered collagen type I turnover, as assessed by the predominance of its synthesis over its degradation, determines the response to CRT in HF patients. Furthermore, the ability of CRT to restore the balance between collagen type I synthesis and degradation is related to its clinical benefits.
It is accepted that myocardial fibrosis is the result of both increased collagen synthesis by fibroblasts and myofibroblasts and unchanged or decreased extracellular collagen degradation.15 Conversely, anti-fibrotic manoeuvres are associated with inhibition of collagen synthesis and/or stimulation of collagen degradation.9 Recent histologically proven data show that the long-term response to CRT is associated with reduction of myocardial fibrosis.13 Therefore, our data on PICP:CITP ratio support the notion that myocardial fibrosis can be present in a subgroup of HF patients with LV dyssynchrony and that these patients can be particularly prone to benefit from the anti-fibrotic ability of CRT.
Fibrillar collagen type I is synthesized in the fibroblast as a procollagen precursor containing an amino-terminal and a carboxy-terminal propeptide.24 After the precursor has been secreted into the extracellular space, the propeptides are removed by specific proteinases, allowing integration of the rigid collagen triple helix into the growing fibril.24 Several observations have led to the proposal that circulating PICP detected in humans with HF is essentially of cardiac origin and that serum PICP is a reliable index of the amount of collagen type I present within the myocardium.9,10 In this conceptual framework, results here presented rise the notion that the clinical and cardiac effects of CRT in HF patients are associated with the diminished myocardial synthesis and deposition of collagen type I fibrils.
It is difficult to speculate on the precise mechanisms underlying the effect of CRT on collagen type I synthesis. However, the hypothesis can be put forward that the rapid reduction of LV dyssynchrony due to CRT decreases the overall mechanical stretch on the LV myocardium and in turn reduces the stretch-induced up-regulation of signalling pathways in cardiac cells (i.e. mitogen-activated protein kinase pathway in fibroblasts) favouring collagen type I synthesis and secretion.25,26 Alternatively, CRT might also interfere with humoral factors that act facilitating myocardial collagen type I production and deposition and that are activated in HF patients (i.e. the sympathetic nervous system and the renin–angiotensin–aldosterone system).27 However, data by Boriani et al.28 show that the beneficial clinical and cardiac long-term effects of CRT are not associated with changes in plasma epinephrine, norepinephrine, renin activity, and aldosterone, thus suggesting that the mechanical factor can be critically involved in the effect of CRT on myocardial collagen type I synthesis.
Collagen degradation is regulated by MMPs, namely collagenase or MMP-1 and gelatinases or MMP-2 and MMP-9, and can occur both intracellularly and extracellularly.29 CITP is a peptide produced when collagen fibrils undergo hydrolysis by MMP-1 and its serum concentration is considered to be a specific marker of extracellular collagen type I degradation.30 The limiting step in the extracellular degradation of collagen is the catalytic cleavage by MMP-1.31 The net level of proteinase activity is dependent on the balance between the active enzyme and a family of TIMPs, namely TIMP-1. Recent findings in HF patients indicate that the ratio MMP-1:TIMP-1 measured in serum reflects well the level of MMP-1 activity within the myocardium.16 Therefore, findings from this study suggest that the positive response to CRT is not related with major changes in the degradation of collagen type I fibres within the myocardium of HF patients.
It has been proposed that induction of MMPs contributes to the maladaptive LV remodelling process that accompanies congestive HF, namely idiopathic dilated cardiomyopathy (DCM).32 However, we found that the increase in collagenolitic capacity (as assessed by the increase in MMP-1, MMP-9, and the MMP-1-to-TIMP-1 ratio) is associated with the increase in EF and reduction in LV dimensions in responders. Therefore, it is likely that the relationship of MMP dysregulation with cardiac outcome in HF patients with cardiomyopathies, different from idiopathic DCM, is far more complex, which is currently recognized.
Some limitations of the current study must be recognized. We are aware that this was a study involving a relatively small number of patients with heterogeneous aetiologies that may have influenced the results. In addition, no experiments were performed to elucidate the precise molecular mechanisms determining CRT-induced changes in myocardial collagen type I synthesis.
In conclusion, the assessment of collagen type I turnover through the measurement of the ratio of serum PICP to serum CITP provides useful predictive information on the clinical response to CRT in HF patients with LV dyssynchrony. Thus, the reported findings set the stage for large-scale clinical studies to definitively validate this approach.
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Work supported by grants from the Departamento de Salud, Gobierno de Navarra and the Spanish Society of Cardiology. This work has been partially funded by the Red Temática de Investigación Cardiovascular (RECAVA), Ministry of Health, Spain, and the European Union (InGenious HyperCare, grant LSHM-CT-2006-037093), and by the arrangement between FIMA and UTE-CIMA project.
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The authors thank Sonia Martínez for her valuable technical assistance.
Conflict of interest: none declared.
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