Συσχέτιση δεικτών ισχαιμίας και λειτουργικότητας του μυοκαρδίου με νατριουρητικό πεπτίδιο του εγκεφάλου

Abstract

Introduction: Natriuretic peptides, mainly the brain natriuretic peptide (B.N.P.) as well asthe N‐terminal‐proBNP (NT‐proBNP) have been thoroughly investigated in the last years inthe context of the heart functioning also as an endocrine organ and have beenappreciatedas as valuable markers for several diseases especially cardiac. In this scientificwork NTproBNP was studied before and after physical exertion/stress test in the context ofcoronary artery disease (C.A.D.)Aim: The evaluation of NTproBNP levels before and after exercise in relation to the degreeof ischemia as well as the detection of a possible correlation with markers of ischemia andmyocardium function. More specifically the aims of the study are:1) The comparison of NTproBNP values and other parameters, which are related to exercisecapacity, with ischemia, dimensions/volumes and myocardial function in between the twomain groups of patients and controls as well as among the subgroups of patients, which arerelated to different severity of ischemia.2)The investigation of a possible change of NTproBNP levels due to exercise.3) the detection of any correlation between NTproBNP before and after the exercise or thecorrelation of any change during the exercise with a)parameters related to exercise capacityb) left ventricular mass c) markers of ischemia d) Lung to heart Ratio of 201Thaliume)markers of cardiac function, including those related to wall thickening and motion.4) To investigate whether NTproBNP values before and/or after exercise, as well as theirdifference is capable of predicting a)ischemia in general (at least mild) b) at least moderateischemia c) severe ischemia.5) To study if patients with severe ischemia (according to high SSS score) show afterexercise lower ejection fraction (EFstress) in comparison with ejection fraction at rest (EFrest).6)The investigation of correlation of NTproBNP levels or other parameters levels with thepresence of myocardial ischemia, taking also into account the influence of eventual confounding factors.Material/Methods: 110 individuals with possible or diagnosis of CAD. Exclusion criteriaconsisted of: a) left bundle branch block (LBBB) b)large anterior infarction c) ejection fraction<50%. Cardiac imaging with gated single‐photon emission computed tomography (SPECT)and physical exercise was performed. Among the study population 85 individuals hadshowed myocardial ischemia according to myocardial perfusion criteria. After physical treadmill exercise with Bruce protocol and gated SPECT consisted the patients of the study.The rest 25 individuals showed no ischaemia, had normal cardiac function or at least noknown, significant stenosis and served as controls. Blood probe from a peripheral vein wasdrawn before and after exercise in the context of stress redistribution gated SPECT, in orderto measure the levels of BTproBNP.Results:1) The concentrations of NTpro‐BNP, before as well as after exercise, were higher in patientsin comparison to controls [(445,293 ± 175,341) vs (309,884 ± 78,240)] fmole/ml, p<0,001 και[(456,251 ± 183,141) vs (327,172 ± 91,981)] fmol/ml p<0,001,respectively. The change ofNTproBNP with exercise was bigger in the group of patients in comparison to the controlsgroup (30,866± 101,753) fmol/ml vs ( 16,932 ±71,292) fmol/ml but did not reach statisticsignificance (p=0,458).When NTproBNP values before exercise were further compared among subgroups withdifferent severity of ischemia with ANOVA and post hok analysis with Bonferroni correctionwas performed, statistically significant difference was detected only between subgroup (3)with severe ischemia (518,188±215,630) and control group (0) (309,884±78,240) fmol/ml.(p <0,001).Similarly NTproBNP values after exercise showed statistically significant difference betweenthe two aforementioned / above mentioned groups : (327,172 ± 91,981) fmol/ml and(547,060 ± 228,683) fmol/ml (p<0,001).2) Statistically significant rise was found between NTproBNP levels before and after exercise[(από 412,9 ± 167,7 fmol/ml σε ( 440,4 ±174,6)] in the context of gated SPECT on thewhole population (επί συνόλου πληθυσμού). When patients (ischemic individuals) wereexamined/studied separately/apart from the controls, the concentration of NTproBNP roseto a significant degree only in patients [(476,159 ± 179,623) fmol/ml vs (445,293±175,341)] fmol/ml με p=0,010.In stratified analysis per category of ischemia , only in the subgroup of severe ischemia (3)significant difference in the NTproBNP concentrations with exercise was detected[(554,645±227,844) vs (518,188±215,630)] fmole/ml.3) a) Significant negative correlations of NTproBNP values exclusively before exercise withthe change of heart rate (r= ‐0,242 p=0,036), the change of systolic blood pressure (r= ‐0,247p=0,034), the change in double product (r= ‐0,246 p=0,035) and the duration of exercise (inseconds) (r= ‐0,255 p=0,027 ), were detected in the group of ischemic patients only. Only in the group of ischemic patients were detected significant negative correlations ofNTproBNP values exclusively before exercise with the change of heart rate (r= ‐0,242p=0,036), with the change of systolic blood pressure (r= ‐0,247 p=0,034), with the change indouble product (r= ‐0,246 p=0,035 ) and with the duration of exercise (in seconds).(r= ‐0,255 p=0,027).No correlation between the parameters of exercise capacity and the values of NTproBNPafter exercise or with their change was detected. Generally no correlation between anyNTproBNP value and exercise parameter was detected.b) In the ischemic group correlation between left ventricular mass and NTproBNP beforeexercise (r= 0,241 p=0,041) .c) In the ischemic group between ischemia markers after exercise as well as of reversibilityat redistribution, expressed either as score or mass orpercent(%) of ischemic tissue andvalues of NTproBNP before and after exercise, of similar strength, with slightly better thecorrelations of NTproBNP before exercise with SSS (r=0,378 p=0,001) as well as withischemic tissue mass in gr (LVmSDefg) (r=0,377 p=0,001) being slightly better.d) Correlation of Lung‐to‐heart Ratio especially when it is measured (a)fter exercise andespecially with values of NTproBNP after exercise (r=0,374 p=0,001), in patients group.No correlation was noticed between transient dilation Index (TIDind) and NTproBNP valueseither before or after exercise.e) Significant correlations in the ischemic group between NTproBNP values before and/orexercise and markers of myocardial function, markers/parameters of wall thickening andmotion, including ejection fraction especially after exercise , enddiastolic volume afterexercise, endsystolic volume before and after exercise, as these parameters were measuredfrom gated SPECT, with better correlation factors between NTproBNP values after exerciseand a marker related to wall thickening and especially with STS score (r=0,509 p<0,001).4) With ROC analysis it was figured out that NTproBNP levels before or /and after exercise,as well as their levels is possible to predictWith ROC analysis it was figured out that NTproBNP levels before or /and after exercise, aswell as their difference is possible to predicta) ischemia in general (at least mild, SSS≥4): the corresponding AUC for NTproBNP beforeand after exercise was 0,795 (C.I. 0,692 ‐0,899), p<0,001 and 0,784 (C.I. 0,678 ‐0,890),p<0,001. (For DBNP η AUC was 0,525 (C.I. 0,382 ‐0,668), p=0,733).For the prediction of even mild ischemia , the following values‐cut off points are indicativelyreported : • NTproBNP before exercise:Value of 290,410 had a sensitivity of 87,5% and specificity of 50%Value of 321,010 had a sensitivity of 79,2% and a specificity of 65% (1‐0,35)Value of 349,970 had a sensitivity of 66,7% και and a specificity of 75% (1‐0,25)c) severe ischemia SSS>13 (The AUC for NTproBNP before and after exercise were similarwith each other, with this of NTproBNP before exercise being slightly better 0,742 (C.I. 0,617‐ 0,867), p<0,001 and 0 ,724 (C.I. 0,604 – 0,844) p=0,001. For the change of NTproBNP theAUC was too low and the p non significant. (0,521 με C.I. 0,395 ‐0,648) p=0,065.5) If patients with severe ischemia expressed with eg a high SSS present after exercise anejection fraction (EF stress) lower than the ejection fraction at rest (EF rest) (55,31 vs 52,55).The mean difference was 2,76 με p=0,019.6) In the end we used multivariate analysis and multiple logistic regression taking theinfluence of age, sex, BMI and the left ventricular mass into account, a positive relationbetween NTproBNP before exercise (p=0,021) and after exercise (p=0,013) was designated,but no correlation was detecte between the change with exercise (p=0,143) with thelikelihood of presence of ischemia.Moreover also with the use of multiple logistic regression analysis the influence of age, sex,BMI and the left ventricular mass into account and the possibility of a positive correlation ofmore parameters of exercise, ischemia, volumes, function (direct and indirect) with thepresence or absence of ischemia was investigated . In the case of a positive (cor)relation therespective odds ratios were calculated.Discussion: 1) The concentratios of NTproBNP before as well as after exercise were higher in patientscomparing to controls.2)A statistically significant correlation between values of NTproBNP with exercise in thecontext of gated SPECT on the whole of the population as well as in the patient groupseparately, but not in the control group separately.3) a)Only in the ischemic group significant negative correlations between NTproBNPvalues exclusively before exercise with exercise parameters were detectedb)In the ischemic group a correlation between left ventricular mass and NTproBNPbefore exercise was detected. c)In the ischemic group too between markers of ischemia at exercise as well as ofreversibility at redistribution (expressed as score, as mass or percentage of ischemic tissue)and NTproBNP before and after it.d)In the patients group (as well some in the control group) correlation of Lung to heart ratioespecially after exercise with NTproBNP after exercise too.In contrast to our first assumptions, the lung to heart ratio (TIDind) did not correlate withany NTrproBNP value before or after exercise.e)On the contrary correlations of NTproBNP and ischemia markers, volumes and functionalmarkers, as the LVEF before and after exercise as well with markers of motion andthickening after exercise , as they were measures by gated SPECT.3)Regarding the capability of NTproBNP to predict ischemia, better discriminating ability inevery cut‐off point of ischemia severity had the NTpoBNP value before exercise.On the whole the NTproBNP value before exercise predicted more reliably at least mildischemia (SSS≥4), that is the value of SSS‐cutt off point .5)Moreover NTproBNP taking the influence of possible confounding factors into accountcorrelated positively with the likelihood of presence of ischemia. Limitations and practical valueof the study: Allthough this/the present Study was aprospective observational study and its design did not include study of the possibleincremental value of NTproBNP in comparison with this of gated SPECT, its contribution tobetter evaluation of the NTproBNP levels, as a marker of inducible ischemia of individualswith possible or diagnosed CAD for more efficient and timely risk stratification andrespective therapy adjustment. If the results of this study are confirmed in a larger numberof people/individuals, an improvement of diagnostic and prognostic value evn of theclassical stress test , without important extra cost and sophisticated technical equipment.

Εισαγωγή:Τα νατριουρητικά πεπτίδια συνιστούν πολύτιμους δείκτες για ποικίλες καρδιακές κυρίως παθήσεις. Σκοπός : Η αξιολόγηση των επιπέδων του ΝΤproBNP πριν και μετά την άσκηση σε σχέση με το βαθμό ισχαιμίας και η ανίχνευση τυχόν συσχέτισής τους με δείκτες ισχαιμίας και λειτουργικότητας του μυοκαρδίου. Μέθοδοι/Υλικό: Σπινθηρογράφημα μυοκαρδίου (gated SPECT) άσκησης (Bruce)‐ επανακατανομής και μέτρηση NTproBNP πριν και μετά την άσκηση διενεργήθησαν σε 85 ισχαιμικούς(στεφανιαία νόσος): «ΙΣΧ» και 25 μη ισχαιμικούς μάρτυρες: «Μ»).Αποτελέσματα: 1)Οι συγκεντρώσεις ΝΤ‐proBNP (fmole/ml), πριν και μετά την άσκηση, ήταν υψηλότερες στους ΙΣΧ συγκριτικά με τους Μ [(445,293 ± 175,341)vs(309,884 ± 78,240)],p<0,001 και [(456,251±183,141)vs(327,172±91,981),(p<0,001)], αντιστοίχως. 2)Το NTproBNPστους ΙΣΧ αυξήθηκε με την άσκηση σημαντικά [από(445,293±175,341) vs(476,159±179,623),p=0,010]3)Στους ΙΣΧ ανιχνεύθηκαν σημαντικές συσχετίσεις NTproBNPμε:α)παραμέτρους άσκησης (p<0,04) β)μάζα αριστερής κοιλίας (r=0,241 p=0,041) γ) δείκτες ισχαιμίας στην άσκηση (κυρίως summed stress score: SSS (r=0,378 p=0,001)) και αναστρεψιμότητας στην επανακατανομή δ) δείκτη πνευμονικής προς καρδιακή καθήλωση(LHR) (r=0,374 p=0,001).Με το δείκτη παροδικής διάτασης της αριστερής κοιλίας (TID) δε σημειώθηκε καμία συσχέτιση με ΝΤproBNP είτε πριν είτε μετά την άσκηση.ε)στους ΙΣΧ μεδείκτες λειτουργικότητας (κλάσμα εξώθησης, τελοδιαστολικό μετά και τελοσυστολικό όγκο,πριν και μετά τη άσκηση),πάχυνσης(summed thickening score, STS‐ήταν η καλύτερη συσχέτιση(r=0,509 p<0,001)) και κινητικότητας τοιχωμάτων 4)Οι τιμές NΤproBNP πριν και μετά την άσκηση με ROC ανάλυση προέβλεψαν: α)ισχαιμία (τουλάχιστον ήπια,SSS≥4): (AUCγια ΝΤproBNP πριν και μετά: 0,795(C.I.0,6920,899),p<0,001 και 0,784(C.I.0,678‐0,890),p<0,001 αντιστοίχως. Τιμές‐ουδοί ενδεικτικά, ΝΤproBNP πριν: 321,010(79,2% και 65%αντίστοιχα), 349,970 (66,7% και 75% αντίστοιχα) γ)σοβαρή ισχαιμία SSS>13 (AUC για ΝΤproBNP πριν και μετά την άσκηση: παραπλήσιες 0,742(C.I. 0,617‐0,867),p<0,001 και 0,724(C.I. 0,604–0,844)p=0,001 αντίστοιχα 5)Οι ΙΣΧ με βαριά ισχαιμία (SSS>13) έχουν μετά την άσκηση κλάσμα εξώθησης μικρότερο συγκριτικά με την επανακατανομή (55,31% vs 52,55%,p=0,019)6) Λαμβάνοντας υπόψη την επίδραση ηλικίας,φύλου,ΒΜΙ και μάζας αριστεράς κοιλίας, αναδείχθηκε θετική συσχέτιση NTproBNP πριν (p=0,021) και μετά (p=0,013) την άσκηση με ισχαιμία.Συζήτηση/συμπεράσματα: Οι τιμές ΝΤproBNP στους ΙΣΧ πριν και μετά την άσκηση ήταν υψηλότερες έναντι των μαρτύρων και αυξήθηκαν με την άσκηση. Ανεδείχθη αξιόλογη συσχέτιση βαρύτητας και έκτασης ισχαιμίας μυοκαρδίου και λειτουργικότητας με gatedSPECT (201Tl) και LHR με τις τιμές του NTproBNP ηρεμίας και άσκησης.