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Modification in serum concentrations of aminoterminal propeptide of type III procollagen in patients with previous transmural myocardial infarction

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Modification in serum concentrations of aminoterminal propeptide of type III procollagen in patients with previous transmural myocardial infarction
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  In myocardial tissue the myocytes are embedded in afibrillar collagen network responsible for normalmyocardial structure and function. 1 There are severalgenetic types of collagen; the main collagens of themyocardial tissue are type I, which is strongly resistantto traction and contributes to wall rigidity, and type III, which is related to elastic properties. 2 In normal adultmyocardium the ratio between type I and type III colla-gen is 2-3:1. 3 Both types are synthesized as precursorsfrom fibroblasts, respectively called type I and type IIIprocollagen, presenting specific C- and N-terminal“extension peptides” at the two ends of the molecule. 2 From the lumen of the rough endoplasmic reticulum,procollagens are transported to the Golgi complex, after which exocytosis occurs by fusion of Golgi vesicles withthe plasma membrane. After secretion, extracellularremoval of extension peptides is mediated by specific N-and C-proteinase, enabling self-assembling of collageninto fibrils. 4 Cleaved N- and C-extension peptides persistin the serum and therefore can be dosed, constituting areliable marker of collagen synthesis. 5  A peculiar featureof the N-terminal propeptide of type III procollagen (PII-INP) is that during collagen type III synthesis, it is nottotally cleaved off from procollagen, so procollagen mol-ecules still retaining PIIINP are found on the surface of mature type III collagen, and these are relatively suscep-tible to proteolytic attack. 6  As a consequence a rapidchange in serum concentration of PIIINP reflects the“acute” breakdown of type III collagen with subsequentrelease of PIIINP into the blood, whereas a more grad-ual increase is indicative of a change in the synthesisrate. 7  Accordingly, it has been demonstrated that PIIINP“reflects the repair process and scar formation followingan acute myocardial infarction.” 8 In this study we analyzed changes over time in theserum concentration of PIIINP in patients with previoustransmural myocardial infarction to assess the role of collagen network rearrangement in modulating postin-farct left ventricular volumes and function. Methods Patients From January to December 1994, 150 consecutive patientsadmitted to the Coronary Care Unit of Modena Policlinico Modification in serum concentrations of aminoterminal propeptide of type III procollagenin patients with previous transmural myocardialinfarction Maria Grazia Modena, MD, FACC, FESC, a  Rosella Molinari, ScD, a  Rosario Rossi, MD, a  Nicola Muia Jr., MD, a   Annadele Castelli, MD, a  Giorgio Mattioli, MD, a  Luisa Bacchella, MD,  b and Fabriziomaria Gobba, MD c  Modena and Pavia, Italy  The aim of our study was to evaluate the modification of serum concentration of aminoterminal propeptide of type III procol-lagen (PIIINP) in 70 patients with previous transmural myocardial infarction. In 38 patients (group 1) PIIINP levels increasedat 6 and 12 months after infarction; in 32 patients (group 2) PIIINP increased at 6 months, returning to baseline at 12months. At the same time we observed a significant left ventricular enlargement and worsening of the performance in group1, whereas in group 2 an improvement was seen in left ventricular volumes and performance. In conclusion, rearrangementof collagen myocardial matrix plays an important role in left ventricular postinfarction modification. This process can be eas-ily followed over time in a noninvasive manner by dosing serum PIIINP concentrations. (Am Heart J 1998;135:287-92.) From the a Institute of Cardiology, Department of Internal Medicine, University of Modena, the b Department of Nuclear Medicine, Fondazione Clinica del Lavoro,Sezione di Pavia, Pavia, and the c Department of Biomedical Sciences, University of Modena.Supported by grant of CNR (Consiglio Nazionale delle Ricerche), FATMA project No. 95.00859.PF41.Submitted June 17, 1997; accepted Aug. 22, 1997.Reprint requests: Maria Grazia Modena, MD, Institute of Cardiology, Department of Internal Medicine, Policlinico - Via del Pozzo 71, 41100 Modena, Italy.Copyright © 1998 by Mosby, Inc.0002-8703/98/$5.00 + 0  4/1/86019  American Heart JournalFebuary 1998 Modena et al. 288 peak levels, the blood samples were collected at the hospitaladmission and after 12, 24, 36, 48, 60, and 72 hours. TheCPK peak level was used as a noninvasive indicator of reper-fusion as proposed by Shell et al. 10 (CPK peak level <13hours from onset of chest pain). Two-dimensional echocardiographic examinations Two-dimensional echocardiography was performed with acommercially available Acuson 128 XP/10c (Acuson Inc.,Mountain View, Calif.) equipped with a 2.5 MHz phased-array transducer. Ventricular volume measurements were performedfrom apical approach two- and four-chambers views as rec-ommended by the American Society ofEchocardiography. 11 The planimetry of the end-diastolic and end-systolic areas was obtained by tracing the endocardial perimeter excludingpapillary muscles and trabeculae carneae. By means of asoftware program already incorporated in the equipment, the volumes were measured with the Simpson’s biapical rule(multiple disks method). 12 The average of three consecutivereadings was used for the statistical analysis. To compare the volumes of the two study groups, we used the values nor-malized for body surface area. The variability (mean absolutedifference) between measurements was measured previously in our laboratory  13  within one observer for end-diastolic vol-ume index (EDVI) (4.5 ml/m 2 ) and end-systolic volumeindex (ESVI) (3.5 ml/m 2 ) and between two observers forEDVI (7.8 ml/m 2 ) and ESVI (5.5 ml/m 2 ). We considered “nor-mal” the following values: 70 ±10 ml/m 2 for EDVI and 35 ±8 ml/m 2 for ESVI; these values correspond to a mean ±SD of a series of 55 age-matched (60 ±10 years, 28 men) healthy subjects. Ejection fraction was calculated as (EDV – ESV)/EDV%. Echocardiographic views and electrocardio-graphic traces were recorded on strip-charts and on video-tape for subsequent examination as necessary. Statistical analysis The continuous variables were expressed as mean ±SD.The normal (Gaussian) distribution of variables was tested by the Kolmogorov-Smirnov test. Comparison between the twostudy groups was assessed by the Student’s t  test for non-paired data. Statistical differences in PIIINP concentrationsover time were tested by the variance analysis. If a significantdifference was found, each value was compared with theothers by multiple comparison procedure ( t  test withBonferroni correction). The Student t  test for paired data was adopted to comparebaseline echocardiographic parameters with those obtainedafter 12 months.The categoric variables are expressed as percentages. Forthese variables differences between groups were tested by the chi-squared test with Yates correction for continuity. Results  At the first control (baseline value) PIIINP concentra-tion was increased in all patients compared with the con- Hospital for a first episode of acute myocardial infarction were considered.Myocardial infarction was diagnosed on the basis of atleast two of the following criteria: (1) prolonged chest pain(>30 minutes), (2) persistent electrocardiographic changescompatible with myocardial ischemia, and (3) increase inserum creatine phosphokinase (CPK) with an MB band >5%.In this population we selected only the patients with trans-mural infarction (development of new and abnormal Q waves) localized according to the 12-lead electrocardiograph-ic criteria in the anterior wall of the left ventricle.Exclusion criteria were as follows: non-Q, nonanterior orprevious myocardial infarction, significant valvular heart dis-ease, cardiomyopathy, malignant and inflammatory rheumaticdiseases, treatment with glucocorticoids or cytostatic drugs,fibrosing alveolitis, liver cirrhosis, impaired liver (prothrombintime <0.6) or kidney function (serum creatinine >120( µ mol/L), recent (<2 weeks) severe trauma, and recent (<6months) surgery procedures; furthermore patients who under- went bypass surgery during follow-up were also excluded.Seventy patients (54 men, mean age 63 ±8 years, range 51to 80 years) were selected and included in the final analysis.Fifty-one (72.8%) of 70 patients received intravenous fibri-nolytic treatment (all these patients underwent r-tPA therapy, which was given as an infusion of 100 mg over a 3-hourperiod), and 19 (27.2%) received only conservative therapy (i.e., morphine, nitrates, β -blockers, and aspirin).Informed consent was obtained from all patients beforethey were entered into the study in accordance with the pro-tocol approved by the University of Modena EthicsCommittee in November 1993. Study design PIIINP concentration was assessed at three different times: within 24 hours from hospitalization and at 6 and 12 monthsafter hospital admission. All patients underwent two-dimen-sional echocardiography before discharge (10 ±2 days afterhospitalization) and 12 months after the acute event. The fol-low-up was concluded in December 1995. Laboratory analysis Blood samples for PIIINP analysis were centrifugated justafter being taken, and serum was stored at –20°C until mea-surement was performed. PIIINP concentration was deter-mined by Rhode et al.’s 9 radioimmunologic method with theuse of a commercially available kit (RIA-gnost Prokollagen-IIIPeptide kits, Behring SpA, L’Aquila, Italy) with normal serumrange (mean ±SD) 0.38 ±0.10 U/ml. The mean recovery of the method at three different PIIINP concentrations rangedfrom 89% to 104%; the reproducibility (CV% among series)based on three consecutive measurements ranged from 7% to15% according to PIIINP concentrations.The mean value of PIIINP in 10 age-matched healthy vol-unteers was 0.40 ±0.10 U/ml. For the serum determinationof CPK, CPK-MB, and glutamic oxaloacetic transaminase  American Heart JournalVolume 135, Number 2, Part 1 Modena et al. 289 trol group: 0.54 ±0.20 versus 0.40 ±0.10 U/ml, respec-tively (  p  < 0.05); at the second control a further increase(0.75 ±0.20 U/ml) was observed. The values provedhigher compared with the group of healthy volunteers (  p  < 0.001) and with baseline values (  p  < 0.01). Until thisdetermination the behavior of PIIINP in all patients wasremarkably homogeneous. Nevertheless, at a 12-monthfollow-up a different behavior emerged; in 38 patientsPIIINP remained elevated (0.76 ±0.10 U/ml), whereas inthe remaining 32 the mean value decreased (0.46 ±0.10U/ml) to levels indistinguishable from those of the con-trol group. On the basis of these results we divided thepatients into two groups: group 1 (persistent PIIINPincrease, n = 38) and group 2 (normal PIIINP at 12-month follow-up, n = 32). PIIINP concentrations foundin the two groups are reported in Table I.Subjects included in group 1 and group 2 had similardemographic characteristics (sex, age, body surfacearea), medical history, clinical characteristics, andechocardiographic profiles before discharge. Thesefindings are presented in Tables II and III.  At a 12-month follow-up a comparison of therapy  was done; in both groups most of the patients werereceiving angiotensin-converting enzyme inhibitors: 20 First controlSecond controlThird control(baseline)(6 mo)(12 mo) Group 1 ( n = 38)0.53 ±0.200.75 ±0.20*0.76 ±0.10Group 2 ( n = 32)0.56 ±0.200.75 ±0.10†0.46 ±0.10 p ValueNSNS<0.01 NS , Not significant.* p < 0.01 vs baseline. † p < 0.01 vs 12 months and baseline. Table I. Serum N-terminal propeptide of type III procollagen (U/ml) in the study groups ParameterGroup 1 ( n = 38)Group 2 ( n = 32)  p Value Age (yr)63 ±1265 ±10NSMen (%)79 ( n = 30)75 ( n = 14)NSBody surface area (m 2 )1.88 ±0.21.80 ±0.1NSHypertension (%)47.3 ( n = 18)50 ( n = 16)NSDiabetes (%)26.8 ( n = 10)25 ( n = 8)NSSmokers (%)36.8 ( n = 14)37.5 ( n = 10)NSHypercholesterolemia (%)26.8 ( n = 10)28.1 ( n = 9)NSSBP (mm Hg)124.2 ±18.8122.6 ±10.1NSDBP (mm Hg)77.4 ±10.870.3 ±10.1NSHR (beats/min)89 ±1182 ±10NSFibrinolysis ev. (%)71 (n = 27)75 (n = 24)NSReperfusion (%)*63.1 (n = 24)62.5 (n = 20)NSCPK (U/L)1926 ±11271612 ±1252NSGOT (U/L)232 ±37220 ±31NS SBP , Systolic blood pressure; DBP , diastolic blood pressure; HR , heart rate; CPK  , peak level of creatine phosphokinase; GOT  , peak level of glutamic oxaloacetic transaminase.*Clinical sign (disappearance of chest pain and resolution of electrocardiographic changes or reperfusion arrhythmias), creatine phosphokinase washout, or both (Shell et al. 10 criterion). Table II. Clinical and medical history details on admission or during hospitalization ParameterGroup 1 ( n = 38)Group 2 ( n = 32)  p Value EDVI (ml/m 2 )93.7 ±2198.9 ±23NSESVI (ml/m 2 )42.7 ±1143.6 ±13NSEF (%)57 ±856 ±8NS EF  , ejection fraction. Table III. Echocardiographic data at discharge (10 ±2 days after hospitalization)  (50.2%) of 38 in group 1 and 18 (56.2%) of 32 ingroup 2 (  p  = NS). Ten (26%) patients in group 1 and8 (25%) in group 2 were being treated with β -block-ers (  p  = NS). Eight (17.8%) patients in group 1 and 6(18.8%) in group 2 were taking a nondihydropyri-dine calcium channel blocker (  p  = NS). All patients were receiving low-dose aspirin. Concerning thepharmacologic therapy, these results show thatgroups 1 and 2 were not significantly different.Furthermore, although echocardiographic datarecorded in the patients of groups 1 and 2 at dis-charge were not statistically different, the resultsobtained 12 months later showed a statistically sig-nificant difference.In group 1 a significant dilation was observed: EDVI was 93.7 ±21 ml/m 2 at baseline compared with 119.7 ±20 ml/m 2 at 12-month follow-up (  p  = 0.001); a similarbehavior was observed for ESVI: 42.7 ±11 ml/m 2 com-pared with 59.9 ±11 ml/m 2 after 12 months (  p  = 0.002).On the contrary, in group 2 a significant improvement was observed; EDVI decreased from 98.9 ±23 ml/m 2 atthe first control to 84.1 ±11 ml/m 2 at 12 months (  p  =0.03), and ESVI decreased from 43.6 ±13 ml/m 2 to 35 ±8 ml/m 2 (  p  = 0.04).Ejection fraction improved only in group 2 (from56% ±8% to 61% ±7%;  p  = 0.04), whereas in group 1it worsened significantly (from 57% ±8% to 48% ±9%;  p  = 0.005).The changes over time in the echocardiographic param-eters are summarized in Figs. 1 and 2. Discussion The extracellular collagen matrix undergoes severedegradation for necrotic conditions. In fact, as a conse-quence of myocyte necrosis, infiltration of inflammato-ry cells and edema formation occurs. Intracellularenzymes activated and released into the interstitiuminduce an activation of collagenases and relatedenzymes, leading to fragmentation of collagen fibers. 14 Myocardial collagen matrix is highly susceptible toischemic injury as shown by the severe damageobserved in infarction but also in experimental tran-sient myocardial ischemia, not resulting in necrosis. 15  After this phase active collagen synthesis and deposi-tion occurs, which leads to fibrosis replacement(“replacement scarring”) of the infarcted area. 16 Myocardial infarction, especially if extensive, causescomplex structural changes in the left ventricle. Infarctexpansion is an early process, characterized by thinningand dilation of the infarcted zone without additionalnecrosis. 17 On histologic examination infarct expansionrepresents slippage between muscle bundles, possibly  American Heart JournalFebuary 1998 Modena et al. 290Figure 1 Group 1: changes in ventricular volumes and ejection fraction.Baseline values are those recorded before discharge (10 ±2days after hospitalization); final observation is after 12 monthsof follow-up. * p = 0.001; ** p = 0.005. Figure 2 Group 2: changes in ventricular volumes and ejection fraction.Baseline values are those recorded before discharge (10 ±2days after hospitalization); final observation is after 12 monthsof follow-up. § p = 0.03; §§ p = 0.04.  American Heart JournalVolume 135, Number 2, Part 1 Modena et al. 291 related to extracellular collagen matrix breakdown. 18 Clinical data have shown that infarct expansion leads toleft ventricular enlargement in the early phase of acuteinfarction, causing an increase in volumes and, if necro-sis is extensive, pump dysfunction. 19 The compensationmechanism is represented by the overrelaxation of seg-ments of healthy myocardium to improve left ventricu-lar function. 20 If this compensation process is sufficientto maintain ventricular performance, the increase in ventricular size will be halted, or even regress. If, onthe other hand, wall stress remains high, ventriculardilation continues and, with time, progresses. 21  According to these observations White et al. 22 demon-strated that ventricular volumes and ejection fraction were the most powerful predictors of prognosis aftermyocardial infarction.In recent years various authors have assessed intersti-tial collagen in experimental studies by histologic exam-inations of myocardial tissue biopsy or autopsy speci-mens; results have shown that rearrangement of themyocardial collagen network plays an important role inthe genesis of systolic and diastolic ventricular dysfunc-tion 23,24 and that collagen levels are abnormally high inthe diseased heart. 3,25 These experimental data havedemonstrated that increased collagen synthesis indicatesa negative prognosis. Biopsies, however, are invasiveand certainly cannot be applied in routine clinical prac-tice in patients with myocardial infarction. The idea toassess the collagen synthesis rate by means of a bio-chemical marker that can be easily measured into theblood, PIIINP, was therefore proposed in this study.PIIINP seems to be a reliable index of synthesis,because the propeptide is cleaved off in a stoichiomet-ric amount during the type III collagen synthesis. 4,8  Various authors 26-29 previously studied PIINP duringthe first hours after acute myocardial infarction. Thesestudies demonstrated an increase in PIIINP in patients with myocardial infarction treated with thrombolysis.Even in our patients we observed a significant increaseof PIIINP (with respect to the control group) measured within 24 hours from the acute episode. Nevertheless,our main interest was to follow collagen synthesis alsoduring the later periods; our data showed that the first“acute” increase was followed by a further and moresubstantial rise in PIIINP level after 6 months. Thisobservation is likely to be related to an active collagenneosynthesis, and it can be reasonably assumed as a“reparative fibrosis” in response to myocardial cellnecrosis (“replacement scarring”). An unexpected resultof this study was the different behavior of PIIINPobserved after 12 months; in group 2 a reduction in PIIINP levels was observed, whereas in group 1 PIIINPlevels still remained high, suggesting an ongoing repairprocess. On the other hand, in group 2 echocardio-graphic results showed an improvement of ventricular volumes and performance, whereas in group 1 a consis-tent worsening was observed. We hypothesize that anincrease in wall stress after the loss of contractile ventric-ular tissue can play an important role in the rise of colla-gen synthesis. In fact, like skeletal muscle, the dimen-sion, alignment, and synthesis of collagen in themyocardium are related to its workload, 30,31 and post-myocardial left ventricular remodeling is a wall-stress-related process. 32,33 In response to wall-stress increase,modification of ventricular myocardium should includean increase in collagen synthesis with a consequently greater concentration of interstitial collagen and a con-tinuous structural remodeling of fibrillar collagen with analtered arrangement with muscle fibers. This fibrosisshould occur in the absence of additional cell necrosisand should be considered a “reactive fibrosis” of theresidual ventricular tissue in response to left ventricularpressure overload. Over time what is initially an adap-tive process that serves to enhance systolic stiffness orthe force-generating capacity of the myocardium canlater adversely influence this mechanical property of themyocardium. In conclusion, rearrangement of myocar-dial extracellular collagen matrix plays an important rolein left ventricular postinfarction modification, exercisinga strong influence on volumes and performance. Themost important finding of this study is that this processcan be easily followed over time in a noninvasive man-ner, simply by dosing serum PIIINP concentrations.The major limitation of our study was that type IIIcollagen is widely distributed in many different tis-sues. 5 Furthermore to our knowledge no studiesexplain (1) how collagen metabolites are transportedfrom the tissues into the blood, (2) the contribution of  various tissues to this process, and (3) how long themetabolites remain in the blood before being degra-dated. There are, however, pathologic conditions suchas fibrosing alveolites, 34 liver cirrhosis, 9 and reparativeprocesses after skin trauma 4 in which a new andactive type III collagen synthesis has been demon-strated. Therefore we excluded from our study patients with a history of fibrosing alveolitis or livercirrhosis and those who underwent surgical proce-dures. On the other hand, it is reasonable to hypothe-size that after a myocardial infarction, collagen synthe-sis is extremely active, and the heart certainly cannot
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