Markers of Extracellular Cardiac Matrix Turnover
Markers of Extracellular Cardiac Matrix Turnover
The baseline characteristics in the 42 patients included in this study are presented in Table 1. The median time from symptom debut to admission was 145 min (range: 25–720 min). Extracellular cardiac matrix-marker analyses from admission samples were available in 35 patients. With the exception of one patient who was unable to attend the final CMR examination at 1 year, all 42 patients underwent all CMR examinations. The first CMR examination was performed at a mean of 2.2 ± 0.1 days following pPCI, the second at 7.3 ± 0.1 days, the third at 61 ± 0.6 days, and the fourth 364 ± 1.2 days following MI. As previously reported, there was a significant reduction in IS (P < 0.001) and LVESVi (P < 0.001), and a significant increase in LVEF (P < 0.002) from 2 days until 1-year follow-up, whereas LVEDVi did not change (Table 2). Inhibitors of the renin–angiotensin–aldosterone system (RAAS) were initiated between 24 and 36 h following pPCI according to department routines. In 13 patients (31%), uptitration to the maximum recommended dose was completed within 1 week following MI. Within 2 months of follow-up, uptitration to target dose as recommended by the ESC guidelines was reached in 27 patients (64%). The combination of either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) with an aldosterone antagonist was initiated in seven patients (17%).
With the exception of TIMP-2 and TIMP-4, ECCM markers showed significant time-dependent changes (P < 0.01 for trend) in their circulating levels during the follow-up (Figure 1). Several significant patterns were demonstrated. First, while ICTP levels were within normal range at baseline, when compared with controls, they showed a rapid and significant increase after 2 days, with persistently raised levels during the whole entire observation period. Secondly, while PINP showed a late increase during the follow-up reaching the highest levels at 1 year, PIIINP showed a rapid increase (2–7 days), with persistently raised levels throughout the observation period, indicating a shift to of type III collagen deposition during the first week following MI. However, except for slightly decreased PIIINP levels during the first week, PINP, and PIIINP levels were within normal limit throughout the observation period. Thirdly, while MMP-2 levels were markedly reduced when compared with controls at baseline, with a significant increase after 2 months before returning to baseline levels after 1 year, baseline MMP-9 levels were markedly increased when compared with controls. This was followed by a rapid decrease after 2 days, with persistently decreased levels when compared with baseline throughout the observation period, with a slight increase from 2 days to 1 week. Fourth, MMP-3 showed a gradual and significant decrease during the follow-up, with levels slightly lower than in controls throughout the observation period. Finally, while there were no changes in TIMP-2 and TIMP-4, TIMP-1 showed a gradual and significant decrease during the follow-up, declining from within to below normal limit from baseline to 1 year.
(Enlarge Image)
Figure 1.
The temporal profiles of markers of extracellular matrix turnover. Circles indicate mean values. Error bars display standard error of the mean. Standard error of the mean for the control group is shaded in grey.
Significant correlations to CMR findings at 1 year were found for PINP, MMP-2, MMP-3, TnT, NT-proBNP, and high-sensitive C-reactive protein (Table 3). The time-point of blood sampling appears to be of essential importance, consistent with the longitudinal profiles of the ECCM markers (Figure 1).
Table 4 displays the results from multivariable linear regression analyses for CMR findings at 1 year. Several findings were revealed. First, baseline levels of PINP were negatively associated with LVEDVi, LVESVi, and IS and positively associated with EF at 1 year. With regard to EF, a similar association was also found for PINP levels after 2 days. Secondly, a similar association pattern was found for MMP-2 levels after 7 days, with a significant negative association with LVEDVi, LVESVi, and IS and a significant positive association with EF at 1 year. As for LVESVi and EF, similar associations were found for MMP-2 levels at baseline. In contrast, an opposite pattern of associations was found for MMP-3, with a positive association with LVEDVi, LVESVi, and IS and a negative association with EF after 1 year. As for LVEDVi and LVESVi, similar associations were also found for MMP-3 levels at 2 days.
Infarct localization as an additional covariate did not affect the results of the multivariable regression models.
An identical multivariable linear regression analysis was conducted for the CMR time-points at 2, 7 days, and 2 months post-AMI. Among biomarkers assessed prior to PCI, PINP was the only independent significant predictor for IS and remodelling parameters at all examination time-points (Table 5).
At 2 days, TnT was the strongest predictive biomarker for all CMR parameters at all estimation time-points (P-values between <0.01 and <0.001) reflecting the strong association between TnT and IS. Among the other biomarkers, significant β-values at all three imaging time-points were seen for MMP-9 (LVEDVi, P-values between <0.05 and <0.001) and high-sensitive C-reactive protein (IS and EF inversely, P-values between <0.05 and <0.01). N-terminal procollagen type I significantly predicted EF at 7 days (P < 0.05). There was a modest correlation between PINP and TnT values at 2 days (r = −0.31, P = 0.04) but no significant correlation between PINP and high-sensitive C-reactive protein (r = −0.20, P = 0.2) or NT-proBNP (r = −0.28, P = 0.07). It is noteworthy that NT proBNP did not predict LV volumes estimated at 2 and 7 days, but was significantly associated with LV volumes at 2 months (P < 0.05–P < 0.01).
At 7 days, MMP-2 and MMP-3 appeared to be the major predictors of outcomes. Both markers were consistent predictors of LV volumes estimated at 7 days and 2 months (P < 0.05 and P < 0.001). Matrix metalloproteinase-3 was the only independent predictor of IS for all given time-points (P < 0.05).
Results
Baseline Characteristics and Cardiac Magnetic Resonance Findings
The baseline characteristics in the 42 patients included in this study are presented in Table 1. The median time from symptom debut to admission was 145 min (range: 25–720 min). Extracellular cardiac matrix-marker analyses from admission samples were available in 35 patients. With the exception of one patient who was unable to attend the final CMR examination at 1 year, all 42 patients underwent all CMR examinations. The first CMR examination was performed at a mean of 2.2 ± 0.1 days following pPCI, the second at 7.3 ± 0.1 days, the third at 61 ± 0.6 days, and the fourth 364 ± 1.2 days following MI. As previously reported, there was a significant reduction in IS (P < 0.001) and LVESVi (P < 0.001), and a significant increase in LVEF (P < 0.002) from 2 days until 1-year follow-up, whereas LVEDVi did not change (Table 2). Inhibitors of the renin–angiotensin–aldosterone system (RAAS) were initiated between 24 and 36 h following pPCI according to department routines. In 13 patients (31%), uptitration to the maximum recommended dose was completed within 1 week following MI. Within 2 months of follow-up, uptitration to target dose as recommended by the ESC guidelines was reached in 27 patients (64%). The combination of either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) with an aldosterone antagonist was initiated in seven patients (17%).
Longitudinal Profile of Extracellular Cardiac Matrix Markers
With the exception of TIMP-2 and TIMP-4, ECCM markers showed significant time-dependent changes (P < 0.01 for trend) in their circulating levels during the follow-up (Figure 1). Several significant patterns were demonstrated. First, while ICTP levels were within normal range at baseline, when compared with controls, they showed a rapid and significant increase after 2 days, with persistently raised levels during the whole entire observation period. Secondly, while PINP showed a late increase during the follow-up reaching the highest levels at 1 year, PIIINP showed a rapid increase (2–7 days), with persistently raised levels throughout the observation period, indicating a shift to of type III collagen deposition during the first week following MI. However, except for slightly decreased PIIINP levels during the first week, PINP, and PIIINP levels were within normal limit throughout the observation period. Thirdly, while MMP-2 levels were markedly reduced when compared with controls at baseline, with a significant increase after 2 months before returning to baseline levels after 1 year, baseline MMP-9 levels were markedly increased when compared with controls. This was followed by a rapid decrease after 2 days, with persistently decreased levels when compared with baseline throughout the observation period, with a slight increase from 2 days to 1 week. Fourth, MMP-3 showed a gradual and significant decrease during the follow-up, with levels slightly lower than in controls throughout the observation period. Finally, while there were no changes in TIMP-2 and TIMP-4, TIMP-1 showed a gradual and significant decrease during the follow-up, declining from within to below normal limit from baseline to 1 year.
(Enlarge Image)
Figure 1.
The temporal profiles of markers of extracellular matrix turnover. Circles indicate mean values. Error bars display standard error of the mean. Standard error of the mean for the control group is shaded in grey.
The Association of Extracellular Cardiac Matrix Markers and Cardiac Magnetic Resonance Variables at 1 Year: Univariate Analysis
Significant correlations to CMR findings at 1 year were found for PINP, MMP-2, MMP-3, TnT, NT-proBNP, and high-sensitive C-reactive protein (Table 3). The time-point of blood sampling appears to be of essential importance, consistent with the longitudinal profiles of the ECCM markers (Figure 1).
The Association of Extracellular Cardiac Matrix Markers and Cardiac Magnetic Resonance Variables at 1 Year: Multivariable Analysis
Table 4 displays the results from multivariable linear regression analyses for CMR findings at 1 year. Several findings were revealed. First, baseline levels of PINP were negatively associated with LVEDVi, LVESVi, and IS and positively associated with EF at 1 year. With regard to EF, a similar association was also found for PINP levels after 2 days. Secondly, a similar association pattern was found for MMP-2 levels after 7 days, with a significant negative association with LVEDVi, LVESVi, and IS and a significant positive association with EF at 1 year. As for LVESVi and EF, similar associations were found for MMP-2 levels at baseline. In contrast, an opposite pattern of associations was found for MMP-3, with a positive association with LVEDVi, LVESVi, and IS and a negative association with EF after 1 year. As for LVEDVi and LVESVi, similar associations were also found for MMP-3 levels at 2 days.
Infarct localization as an additional covariate did not affect the results of the multivariable regression models.
The Association of Extracellular Cardiac Matrix Markers and Cardiac Magnetic Resonance Findings at the Four Different Time-points
An identical multivariable linear regression analysis was conducted for the CMR time-points at 2, 7 days, and 2 months post-AMI. Among biomarkers assessed prior to PCI, PINP was the only independent significant predictor for IS and remodelling parameters at all examination time-points (Table 5).
At 2 days, TnT was the strongest predictive biomarker for all CMR parameters at all estimation time-points (P-values between <0.01 and <0.001) reflecting the strong association between TnT and IS. Among the other biomarkers, significant β-values at all three imaging time-points were seen for MMP-9 (LVEDVi, P-values between <0.05 and <0.001) and high-sensitive C-reactive protein (IS and EF inversely, P-values between <0.05 and <0.01). N-terminal procollagen type I significantly predicted EF at 7 days (P < 0.05). There was a modest correlation between PINP and TnT values at 2 days (r = −0.31, P = 0.04) but no significant correlation between PINP and high-sensitive C-reactive protein (r = −0.20, P = 0.2) or NT-proBNP (r = −0.28, P = 0.07). It is noteworthy that NT proBNP did not predict LV volumes estimated at 2 and 7 days, but was significantly associated with LV volumes at 2 months (P < 0.05–P < 0.01).
At 7 days, MMP-2 and MMP-3 appeared to be the major predictors of outcomes. Both markers were consistent predictors of LV volumes estimated at 7 days and 2 months (P < 0.05 and P < 0.001). Matrix metalloproteinase-3 was the only independent predictor of IS for all given time-points (P < 0.05).
Source...