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Signal-averaged electrocardiography and echocardiography in the evaluation of myocardial involvement in progressive systemic sclerosis
International
Journal
of
cardiology ELSEVIER
InternationalJournal of Cardiology53 (1996)171-177
Signal-averaged electrocardiography and echocardiography in the evaluation of myocardial involvement in progressive systemic sclerosis Michele Paradise* *, Francesco Gabriellib, Luigi Coppotellia, Giancarlo Aguglia”, Mario Pergolinia, Massimo Leonardoa, Stefania Basili”, Enrico Alcinib, Cesare Masalad, Corrado Cordovaa PIstituto di Terapia Medica, Servizio di Profilassi della Cardiopatia Ischemica, Policlinico Vmberto t, Vniversitci ‘La Sapienza’ I-00161 Roma, Italy bDipartimento di Scienze Cardiovascolari e Respiratorie. Vniversiti! ‘La Sapienza’, Roma, Italy cIstituto di I Clinica Medica, Vniversitci ‘La Sapienza’, Roma, Italy dDipartimento di Malattie Infettive e Tropicali, Vniversitd ‘Lo Sapiensa’, Roma, Italy
Received2 August 1995;revisionaccepted7 November1995
To assessthe myocardial involvement in progressive systemicsclerosiswe evaluated the presenceof late potentials by signal-averaged electrocardiography (signal-averaged ECG) and the left ventricular function by M-mode, two diiensional and Doppler echocardiography. Fifteen outpatients, 7 with diffuse progressive systemic sclerosis and 8 with CREST syndrome variant, without clinical or electrocardiographic evidence of cardiac diseasewere studied and comparedwith 18normal subjects.Late potentials occurred in 5 out of 15progressivesystemicsclerosispatients (33%) with a signifkant difference versus controls (P c 0.05) and were present only in the patients with diffuse progressive systemicsclerosis(P s 0.001 vs. controls). All progressivesystemicsclerosispatients showed a normal left ventricular systolic function. Abnormal left ventricular filling was found in 9 progressivesystemicsclerosispatients (5 with diffuse progressivesystemicsclerosisand 4 with CREST). A more severeimpairment of the mean values of diastolic function indexeswas found in diffuse progressivesystemicsclerosisthan in CREST. In all diffuse progressivesystemicsclerosis patients at least one method showed altered results, whereashalf the CREST patients showed no pathological findings with both techniques. These results confirm a lower myocardial involvement in the CREST syndrome than in diffuse progressivesystemic sclerosis and consequently this is probably related to a better prognosis. Keywordr: Signal-averaged electrocardiography; Echocardiography; Progressive systemic sclerosis; Late potentials; Left ventricular function
* Correspondingauthor, Viale dei Primati Sportivi, 54, I00144,Roma,Italy. Tel.: +39 6 5914563. 0167-5273MB15.00 0 1996Elsevier ScienceIreland Ltd. All rights reserved SSDI 0167-5273(95)02521-W
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M. Pan&so et al. /International Jountal of Cardiology 53 (19%) 171- I77
1. Imroduction Progressive systemic sclerosis is a disease characterizedby extensivevascular and connective tissue damage involving various organs [l]. The classic picture of the disease is characterized by diffuse sclerodermatousalterations while the predominance of calcinosis, Raynaud’s phenomenon, esophagealdysmotility, sclerodactyly and telangiectasiascharacterizes the CREST syndrome variant [2]. The heart is frequently involved in progressive systemic sclerosis and one of the major cardiac injures is representedby focal myocardial fibrosis randomly distributed throughout the myocardium [3]. Signal-averaged electrocardiography (signalaveraged ECG) is used for recording ventricular late potentials, which are the expression of slowed and disorganized conduction through zones of myocardial scarring providing the substrate for reentrant ventricular arrhythmias [4]. Some investigators have hypothesized that myocardial scarring in systemic sclerosis could produce areas of delayed myocardial activation [5]. Echocardiography is a non-invasive technique for the evaluation of the left ventricular function. Previous echocardiographic studies reported an impairment of systolic left ventricular function and an abnormal pattern of left ventricular filling indices in patients with progressive systemic sclerosis [6-81. The aims of the study were: (a) the evaluation by signal-averagedECG and echocardiography of the myocardial involvement in scleroderma patients without clinical and electrocardiographic evidence of cardiac disease,and (b) the assessmentof the signal-averagedECG and echocardiographic findings in two groups of scleroderma patients, i.e. those with the diffuse form of progressivesystemic sclerosisand those with the CREST variant. 2. Materials and methods 2.1. Patients This study was carried out on 15 outpatients (1 male and 14 female, mean age 51 f 9 years, range 35-70) attending the Center for Autoimmune Diseasesof the University ‘La Sapienxa’ of Rome.
The diagnosis of progressivesystemicsclerosiswas made according to the criteria of the American Rheumatism Association [2]. Informed consent was obtained from all subjects enrolled and the study was approved by the local ethics committee. Seven patients (1 male and 6 females, mean age 55 f 3) had diffuse progressive systemicsclerosis; 6 of thesewere positive for antinuclear antibodies of the ‘speckled’ or ‘nucleolar’ patterns (indirect immunofluorescence on Hep-2 cells) and 3 had anti Scl-70 (antitopoisomerase I) antibodies (ANA-Profile, Euroimmun GmbH, Ltibeck, Germany). Eight patients, all female (mean age 49 * 1I), had the CREST syndrome; all of these were positive for anticentromere antibodies. Eighteen normal subjects, 13 male and 5 female aged 33-68 (mean 46 f 13) were studied as controls. None of the subjectsincluded in this study had evidence of cardiac disease as assessedby history, physical examination and standard 12-lead ECG. Patients with echocardiographic evidence of pericardial or valvular involvement were excluded. 2.2. Signal-averagedECG The signal-averagedECG was recorded using a Schiller computerized multi-channel device (model Cardiovit CS 6/12 VME 5.5) with 800 Hz sampling frequency, 12 bit resolution and O-500 Hz frequency response.During the first 10 s of the measurement a sample beat (template) was decided. A signal averaging of the actual heart beat only took place when there was a correlation of more than 98% between the actual heart beat and the template. A number of cardiac cycles (250) was averagedto decreasenoise to a level < 0.2 PV with subjects lying quietly supine. After the signal averaging the ECG data were filtered using a high passwith limit frequenciesof 40 Hz and a low pass filtering at 250 Hz According to Simson’s methods [9], the so-called vector magnitude was calculated after the filtering for the data evaluation. The start of the vector magnitude was equal to the QRS start in the unfiltered leads; the end of the vector magnitude was the endpoint of a 6 ms duration in which the vector magnitude was larger than the sum of the noise plus 2.5 times the standard deviation. Finally, the highly frequent QRS
M. Paradise et al. /International
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Journal of Cardiology 53 (1996) 171-177
duration of thesevector amplitudes, the root mean squarevoltage of the last 40 ms and the part of the vector amplitude below 40 c(V (low amplitude signals) were calculated. Criteria for an abnormal signal-averagedECG included two of the following: (1) QRS duration > 114 ms, (2) root mean square voltage < 20 FV, and (3) low amplitude signals duration > 38 ms [lo-121. 2.3. Echocardiography The study was performed using a HewlettPackard Sonos 100 ultrasound imaging system with a 2.5 MHz transducer. All subjects were studied by M-mode, two-dimensional and Doppler (continuous and pulsed wave) echocardiography. M-mode echocardiography was performed according to the American Society of Echocardiography [ 131,and left ventricular end-diastolic and end-systolic cavity dimension, left atrial cavity dimension, ventricular septal and left ventricular posterior wall thickness were obtained. Ejection fraction was calculated according to the cube formula. Fractional shortening was defined as the difference between the left ventricular diastolic and systolic dimensions divided by the diastolic dimension. Velocity of circumferential fibre shortening was calculated as fractional shortening divided by left ventricular ejection time. An evaluation of segmentalleft ventricular function was performed using two-dimensional long axis and short axis parasternal views and fourchamber apical view. Left ventricular diastolic filling was studied by pulsed Doppler with an apical four-chamber view
with the samplevolume placed at the mitral leaflet tips. The following measurementswere obtained as the average of three beats [14-161: (1) peak of early diastolic flow velocity EVmax;(2) peak of late diastolic flow velocity A,,-; (3) Ey-/Avmax; (4) the velocity time integral of early diastolic flow (E integral); (5) the velocity time integral of late diastolic flow (A integral); (6) E integral/A integral; (7) rate of decreaseof flow velocity in early diastole (EF slope). The isovohtmic relaxation time, the time interval from the aortic valve closure to the onset of the transmitral flow, was calculated by adjusting the Doppler beam across the outflow tract. The pulsed Doppler of the aortic flow was employed to obtain some indexes of left ventricular systolic function. The following measurementswere calculated on the average of three beats [17,18]: (1) peak flow velocity, (2) flow velocity time integral, (3) acceleration time, (4) ejection time. 2.4. Statistical analysis Values are given as mean and standard deviation. The groups were compared using the independent Student’s t-test for continuous data and the x2 test for categorial data. A value of P < 0.05 was considered statistically significant. 3. Resulta 3.1. Signal-averagedECG Signal-averagedECG results are summarized in Table 1. Late potentials in progressive syste&
Table 1 Signal-averagedECG parameters in patients and in control subjects
QRS(W RMS 0 LAS (m) LP
Controls (n = 18)
PSS (n= 15)
dPSS (n = 7)
CREST (n = 8)
95.16 f 6.54 32.32 f 13.99 30.79 zt 6.47 1118
95.27 f 12.55 26.77 f 15.79 35.33 f 10.36 5/15*
103.43f 12.35. 17.47 + 11.472 44.14 f 7.71*** 5/7*++
88.12 a 7.7+ 34.91 l 14.94 27.62 zk 4.27 O/8
dPSS, diffuse progressive systemic sckrosis; LAS, low amplitude signals; LP, late potentials; PSS, progressive systemic sclerosis; QRS, fdtered QRS duration; RIMS, root mean square voltage. +P < 0.05 vs. controls; *+P s 0.01 vs. controls; **+P s 0.001 vs. controls.
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M. Pat&&o et al. /International Journal of Cardiology 53 (1996) 171-177
Table 2 Echocardiographic indexes of left ventrictdar systolic function in patients and in control subjects
EF (%) Fs (%)
VCF (circk) PFV (Ao) (cm/s) V-H (A4 (cd AT 640) (W ET (A4 (m.9
Controls (n = 18)
IJSS(n = 15)
76.58 f 5.58 39.0 f 5.12 1.21 * 0.22 99.58 ZIE10.6 19.58 f 2.06 102.08 f 15.73 307.08 f 35.06
78.25 zt 40.25 * 1.13 l 105.50 f 21.58 f
5.17 4.9 0.17 19.29 3.82
dPSS (n = 7) 75.83 f 4.17 37.83 t 3.37
1.10 f 0.17 106.33 * 19.5 21.67 f: 3.5
109.50f 30.22
113.83f 41.69
307.33 f 34.31
305.83 f 36.39
CREST (n = 8) 80.67 f 5.24 42.67 f 5.24
1.17 l 0.19 104.67 f 20.9 21.5 EIE4.46 98.50 f 15.98 308.83 zt 35.50
AT (Ao), aortic acceleration time; dPSS,diffuse progressivesystemicsclerosis;EF, left ventricular ejection fraction; ET (Ao), aortic ejection time; FS, left ventricular fractional shortening; PFV (Ao), peak aortic flow velocity; PSS,progressivesystemicsclerosis;VCF, velocity of cimmnferential fibre shortening; VT1 (Ao), velocity time integral of aortic flow.
sclerosisoccurred in 5 out of 15 patients (33%) vs. 1 out of 18control8 (5.5%). The difference between the two groups was statistically significant (P < 0.05). Analysis of the results in the two subgroups of patients revealed that late potentials were present in 5 of 7 patients with diffuse progressive systemic sclerosis (71.4%), the difference vs. normal controls being statistically significant at the level of P < 0.001. In contrast, none of the patients with CREST syndrome showed late potentials. The mean values of QRS, root mean square voltage and low amplitude signals recorded among the 15 patients with progressive systemic sclerosis
did not statistically differ from those found in normal controls. However, the analysis of the results in the two subgroups of progressive systemic sclerosispatients showed that the subgroup of patients with diffuse progressive systemic sclerosis had highly significant differences as compared with normal controls. QRS, 103.43ms f 12.35vs. 95.16 ms A 6.54 (P = 0.03); root mean square voltage, 17.47PV AE11.47 vs. 32.32 PV f 13.99 (P = 0.02); low amplitude signals: 44.14 ms f 7.71 vs. 30.79 ms i 6.47 (P < 0.001). No signi& cant differenceswere found in the mean values of the signal-averaged ECG parameters in the
Table 3 Echocardiographic indexes of IeR ventricuhu diastolic function in patients and in control subjects
E integral (cm) A integral (cm) E/A integral EF slope (cmkz, IVRT (ms)
Controls (n = 18)
Pss (n = 15)
81.50 47.67 1.72 10.22 3.64 3.20 410.83 69.17
69.93 f 58.40 zt 1.23 f 7.35 zt 4.75 + 1.73 * 352.40 f 86.0 *
+ 11.77 +c 7.56 zt 0.31 f 4.18 l 1.17 f 0.71 f 64.23 a 5.97
19.45 12.31;. 0.37*** 2.31. 1.96 0.755' 73.92+ 14.04***
dPSS (n = 7) 63.0 zt 19.43' 60.0 f 15.19.
1.11 zt 0.42** 6.71 5.17 1.51 317.43 93.57
zk 2.80 f 2.49 +z 0.8*** f 64.1955 ~JZ13.76***
CREST (n = 8) 76.0 i 18.52 57.0 * 10.03* 1.35 f 0.30** 7.79 l 1.77 4.39 f 1.42 1.92 zk 0.58*** 384.75 + 70.84 79.37 f 11.16.
A integral, velocity time integral of late diastolic flow; A ,,-, peak late diastolic flow velocity; dPSS, diffuse progressive systemic sclerosis;E integral, velocity time integral of early diastolic flow; EF slope, rate of decreaseof flow velocity in early diastole; Ev-, peak early diastolic flow velocity; IVRT, isovolumic relaxation time; PSS, progressive systemic sclerosis. *P < 0.05 vs. controls; l *P s 0.01 vs. controls; l **P S 0.001 vs. controls.
hf. Paradiso et al. /International Journal of Cardiology 53 (19%) 171-177
CREST subgroup vs. controls, except for a shorter QRS duration (88.12 ms f 7.7 vs. 95.16 ms * 6.54; P = 0.02). 3.2. Echocardiography
Compared with the control group, progressive systemic sclerosis patients showed no differences in cardiac chamber dimensions and wall thickenings. All progressive systemic sclerosis patients and controls showed a well preservedleft ventricular systolic function (Table 2). Abnormalities of left ventricular filling dynamic were found in 9 progressive systemic sclerosis patients (5 with diffuse progressive systemic sclerosis and 4 with CREST) with a P value < 0,001. Compared with control subjectsthesepatients showed a significant decrease of Ev,,JAvmax (1.23 * 0.3 vs. 1.72 f 0.31; P = 0.001) and E integral/A integral (1.73 AZ0.7 vs. 3.20 A 0.71; P < O.OOl),a lower EF slope (352.40 cm/s* f 73.92 vs. 410.83 cm/s2 * 64.23) and a prolonged isovolumic relaxation time (86.0 ms * 14.04 vs. 69.17 ms f 5.97; P = 0.001). The diffuse progressive systemic sclerosis subgroup showed lower values of E V,,JAVmax,E integral/A integral and EF slope, and higher values of isovohunic relaxation time in comparison with the CREST subgroup (Table 3). 4. Discrmxlon Myocardial involvement in progressive systemic sclerosis is morphologically characterized by a spectrum of focal injuries ranging from contraction band necrosis to replacement fibrosis, and no extramural or intramural vascular abnormalities can be seen to account for the damage [3]. This kind of involvement is frequently found in autopsy studies [3] but is lesseasyto detect clinically. Clinical evidence of myocardial involvement determines a poor prognosis [19,20]. In the past few years several studies with non-invasive techniques have provided strong evidence for a subclinical myocardial involvement in the population with progressive systemic sclerosis [5-8,21-251. The principal clinical application of signalaveragedECG is to provide risk stratification for arrhythmic eventsin the post-infarction period [9].
175
However, the presenceof late potentials has been associatedwith myocardial fibrosis even in the absenceof myocardial infarction [26]. M-mode, twodimensional and Doppler echocardiography represent relatively simple methods for evaluation of the effect of the progressive systemic sclerosis on the left ventricular function [7,8]. The alterations of left ventricular function can be explained by myocardial inflammation, fibrosis or myocardial ischemia due to a Raynaud’s-like phenomenon of the intramyocardial arteries [3]. Compared with controls, a significantly increased prevalence of late potentials and altered left ventricular diastolic filling was found in our progressivesystemic sclerosispatients and, in this respect, our results are consistent with other reported data [5,8,27-301. A previously unrecorded finding emerging from this study is the different pattern of cardiac abnormalities detectable by signal-averagedECG in the two subgroups of progressive systemic sclerosis patients. In fact, signal-averagedECG showed opposite trends in diffuse progressive systemic sclerosisand in CREST. Only patients with diffuse progressivesystemicsclerosisshowed a significant positivity both regarding late potentials presence and as mean values of each parameter. Root mean square voltage and low amplitude signals showed no significantly different values in the CREST patients in comparison with the controls. The different prevalence found in women, who are characterizedby a lower left ventricular mass [31], can explain the shorter QRS duration shown in CREST patients than in controls. Our signalaveraged ECG results showed that myocardial fibrosis can determine the signal fragmentation related to late potentials presenceonly in the diffuse form of progressive systemic sclerosis. In the progressive systemic sclerosispatients we found a significant prevalence of abnormal left ventricular diastolic filling characterized by reduced E,,-lAV,, and E integral/A integral, a lower deceleration rate of early diastolic flow velocity (EF slope) and a prolonged isovolumic relaxation time. None of thesepatients had systemic hypertension, left ventricular hypertrophy, clinical evidenceof coronary artery diseaseor altered left ventricular systolic function.
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M. Pan&so et al. /International Journal of Cardiology 53 (19%) I71-177
In the analysisof eachsinglepatient the signalaveragedECG data and echocardiographicparameterswere found to agreein only a few cases. However,the meanvaluesof diastolic function indexeswere found to be more severelyimpaired in diffuse progressive systemic sclerosis than in CREST (Table 3). This observation is in accordancewith the presenceof the late potentialsonly in the diffuse progressivesystemicsclerosisform (Table 1). only a few studiesrefer to cardiac involvement in scleroderma according to the form of the disease.An increasedprevalenceof ventricular arrhythmias was reported in patients with diffuse progressivesystemicsclerosis[23] and studieswith thallium scanninghaveshown a better left ventricular function in CREST syndromethan in diffuse progressivesystemic sclerosis [22]. In contrast, Kostis et al,, in a study performed with ambulatory electrocardiography,did not find significant differencesin the prevalenceof arrhythmiasin the
Table 4 Late potentials and left ventricular diastolic dysfunction in the two clinical expressionsof progressive systemic sclerosis
caseno. dPSS 1 2 3 4 5 6 7 CREST 1 2 3 4
LP
DD
+
+
+ + + +
+ + + + +
+ +
5 6 7
+
8 dpsS, dithse progressive systemic sclerosis; DD, diastolic dysfunction; LP, late potentials; PSS, progressive systemic sclerosis.
two main clinical forms of progressivesystemic sclerosis[24]. In our patients,who had beenselectedfor having no clinical evidenceof cardiacinvolvementand electrocardiographicabnormalities,the combined utilization of echocardiographyand signal-averaged ECG permitted a more completeevaluation of myocardialinvolvement.In all the patientswith the diffuseform of the diseaseat leastone method was found to givealtered results.The presenceof abnormalfindingswith both the methodscould be an indication of a more advancedmyocardial fibrosis.On the other hand, half of the patientswith CREST syndromedid not show any pathological findings with either technique(Table 4). Theseresults are consistentwith a less severemyocardial involvementin CREST syndromeas well as with the reported clinical finding 1221of a significantly longer duration of diseasein thesepatients compared with the diffuse progressivesystemicsclerosisgroup. The absenceof both echocardiography and signal-averagedECG alterationsprobably accounts for a better prognosis. The results obtained with the two methods could be related to a different expressionof myocardial involvement.Further follow-up studiesare neededfor a better definition of the clinical implications of the signal-averagedECG and echocardiographicdata. References [I] Medsger TA. Progressivesystemicsclerosis.Clin Rheum Dis 1983;9: 655-670. [21 Subcommitteefor Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic criteria committee. Prelimimuy criteria for the classiication of systeh sclerosis (schoderma). Arthritis Rheum 1980,23z 581-590. 131 Bulkley BH. Ridol!i RL, Salyer WR, Hutchins GM. Myocardhl lesions of progressive systemic sclerosis. A cause of cardiac dysfunction. Circulation 1976; 53: 483-490. 141 Simson MB, Untereker WJ, Spielman SR et al. Relation between late potentials on the body surface and directly recorded fragmented electrocardiograms in patients with ventricular tachycardia. Am J Cardioll983; 51: 105-l 12. 151 Moser DK, StevensonWG. Woo MA et al. Frequency of late potentials in systemic sclerosis.Am J Cardiol 1991; 67: 541-543. [61 Gottdiener JS, Moutsopoulos HM, Decker JL. Echocar-
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et al. /International
diographic identification of cardiac abnormality in scleroderma and related disorders. Am J bled 1979;66: 391-398. [7] Kazzam E, Caidabl K, Hallgren R, GustaRson R, Landelius J, Waldestrom A. Non-invasive assessmentof systolic left ventricular function in systemicsclerosis.Eur Heart J 1991; 12: 151-156. [S] ICaxsamE, Waldestrom A, Landelius J, Hallgren R, Arvidsson A, Caidahl IL. Non-invasive assessmentof left ventricular diastolic function in patients with systemic sclerosis.J Int Med 1990,228: 183-192. [9] Siion MB. Use of signals in the terminal QRS complex to identify patients with ventricular tachycardia after myocardial infarction. Circulation 1981;64: 235-242. [lo] Breithardt G, Cain ME, El-Sherif N et al. Standards for analysis of ventricular late potentials using highresolution or signal-averagedelectrocardiography. J Am Co11Cardiol 1991; 17: 999-1006. [11] Buxton AE, Sin MB, Falcone RA, Mar&in&i FE, Doherty JU, JosephsonME. Results of signal-averaged electrocardiography and electrophysiologic study in patients with nonsustained ventricular tachycardia after healing of acute myocardial infarction. Am J Cardiol 1987;60: 80-85. [12] Gang ES, Lew AS, Hong M, Wang FZ, Siebert CA, Peter T. Decreasedincidence of ventricular late potentials after successfiJIthrombolytic therapy for acute myocardial infarction. N Engl J Med 1989; 321: 712-716. [13] Sahn DJ, DeMaria A, Kislo J, Weyman AI. The conunittee on M-mode standardization of the American Society of Echocardiography. Recommendation regarding quantitation in M-mode echocardiography: results of a survey of echocardiography measurements. Circulation 1978; 58: 1072-1078. [14] Spirit0 P, Maron BJ. Doppler echocardiography for amessingleft ventricular diastolic function. Ann Intern Med 1988; 109: 122-126. [IS] Lew WYW. Evaluation of left ventricular diastolic fimction. Circulation 1989; 79: 1393-1397. 1161 Spirit0 P, Lupi G, Melevendi C, Vecchio C. Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major. Circulation 1990.82: 88-94. [17] Maione S, Valet&i G, Giunta A et al. Cardiac involvement in rheumatoid arthritis: an echocardiographic study. Cardiology 1993;83: 234-239. [18] Missri J. Clinical Doppler Echocardiography. Spectral and Color Flow Imaging. New York: McGraw-Hill, pp. 87-88. [19] Medsger TA, Masi AT, Rodnan GP, Benedek TG, Robinson H. Survival with systemic sclerosis(scleroderma). A life-table analysis of clinical and demographic
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factors in 309 patients. Ann Intern Med 1971; 75: 369-376. [20] Wynn J, Fineberg N, Matxer L. Prediction of survival in progressive systemic sclerosisby multivariate analysis of clinical features. Am Heart J 1985; 110: 123-127. [21] Follansbee WP, Curt& EI. Medsger TA jr et al. Physiologic abnormalities of cardiac function in progressive systemic sclerosiswith diffuse scleroderma. N Engl J Med 1984;310: 142-148. (22) Follansbee WP, Cur&s EI, Medsger TA Jr, Owens GR, SteenVD, Rodnan GP. Myocardial function and perfusion of the CREST syndrome variant of progressive systemic sclerosis. Exercise radionuchde evaluation and comparison with diffuse scleroderma. Am J Med 1984; 77: 489-496. [23] Follansbee WP, Curtiss EI, Rahko PS et al. The electrocardiogram in systemic sclerosis(scleroderma). Study of 102consecutivecaseswith functional correlations and review of the literature. Am J Med 1985;79: 183-192. [24] Kostis JB, Se&old JR, Turkevich D et al. Prognostic importance of cardiac arrhythmias in systemic sclerosis. Am J Med 1988;84: 1007-1015. [25] Anvari A, Graninger W, Schneider B, Sochor H, Weber H, Schmidinger H. Cardiac involvement in systemic sclerosis.Arthritis Rheum 1992; 35: 1356-1361. [26] Mehta D, McKenna WJ, Ward DE, Davies MJ, Camm AJ. SignMcance of signal-averaged electrocardiography in relation to endomyocardial biopsy and ventricular stimulation studies in patients with ventricular tachycardia witbout clinically apparent heart disease.J Am Coll Cardiol 1989; 14: 372-379. 1271 Pignone A, Matucci-Cerinic M, Becucci A et al, Il rilevamento dei potenxiali ventricolari tardivi nella sclerosisistemica:metodica non invasiva per lo studio de1 coinvolgimento cardiaco. Ann Ital Med Int 1994; 9: 141-145. [28] Kazzam E, Caidahl K, Hallgren R, Johansson C, Waldestrom A. Mitral regurgitation and diastolic flow profile in systemic sclerosis. Int J Cardiol 1990; 29: 357-363. (291 Maione S, Valentini G, Giunta A et al. Evaluation of cardiac structuresand function in systemicsclerosisby Dop pler echocardiography. Cardiology 1991;79: 165-171. (30) StancscuC, Dan GA. Myocardial involvement in systemic lupus erythematosus and systemic sclerosis. Pulsed Doppler echccardiographic evaluation of left ventricular diastolic function. Rev Roum Med Int 1992; 30: 243-248. 1311 Raineri AA, Traina M, Rotolo A, Lombard0 RMR. Quantitative analysis of ventricular late potentials in healthy subjects. Am J Cardiol 1990,66: 1359-1362.
Journal
of
cardiology ELSEVIER
InternationalJournal of Cardiology53 (1996)171-177
Signal-averaged electrocardiography and echocardiography in the evaluation of myocardial involvement in progressive systemic sclerosis Michele Paradise* *, Francesco Gabriellib, Luigi Coppotellia, Giancarlo Aguglia”, Mario Pergolinia, Massimo Leonardoa, Stefania Basili”, Enrico Alcinib, Cesare Masalad, Corrado Cordovaa PIstituto di Terapia Medica, Servizio di Profilassi della Cardiopatia Ischemica, Policlinico Vmberto t, Vniversitci ‘La Sapienza’ I-00161 Roma, Italy bDipartimento di Scienze Cardiovascolari e Respiratorie. Vniversiti! ‘La Sapienza’, Roma, Italy cIstituto di I Clinica Medica, Vniversitci ‘La Sapienza’, Roma, Italy dDipartimento di Malattie Infettive e Tropicali, Vniversitd ‘Lo Sapiensa’, Roma, Italy
Received2 August 1995;revisionaccepted7 November1995
To assessthe myocardial involvement in progressive systemicsclerosiswe evaluated the presenceof late potentials by signal-averaged electrocardiography (signal-averaged ECG) and the left ventricular function by M-mode, two diiensional and Doppler echocardiography. Fifteen outpatients, 7 with diffuse progressive systemic sclerosis and 8 with CREST syndrome variant, without clinical or electrocardiographic evidence of cardiac diseasewere studied and comparedwith 18normal subjects.Late potentials occurred in 5 out of 15progressivesystemicsclerosispatients (33%) with a signifkant difference versus controls (P c 0.05) and were present only in the patients with diffuse progressive systemicsclerosis(P s 0.001 vs. controls). All progressivesystemicsclerosispatients showed a normal left ventricular systolic function. Abnormal left ventricular filling was found in 9 progressivesystemicsclerosispatients (5 with diffuse progressivesystemicsclerosisand 4 with CREST). A more severeimpairment of the mean values of diastolic function indexeswas found in diffuse progressivesystemicsclerosisthan in CREST. In all diffuse progressivesystemicsclerosis patients at least one method showed altered results, whereashalf the CREST patients showed no pathological findings with both techniques. These results confirm a lower myocardial involvement in the CREST syndrome than in diffuse progressivesystemic sclerosis and consequently this is probably related to a better prognosis. Keywordr: Signal-averaged electrocardiography; Echocardiography; Progressive systemic sclerosis; Late potentials; Left ventricular function
* Correspondingauthor, Viale dei Primati Sportivi, 54, I00144,Roma,Italy. Tel.: +39 6 5914563. 0167-5273MB15.00 0 1996Elsevier ScienceIreland Ltd. All rights reserved SSDI 0167-5273(95)02521-W
172
M. Pan&so et al. /International Jountal of Cardiology 53 (19%) 171- I77
1. Imroduction Progressive systemic sclerosis is a disease characterizedby extensivevascular and connective tissue damage involving various organs [l]. The classic picture of the disease is characterized by diffuse sclerodermatousalterations while the predominance of calcinosis, Raynaud’s phenomenon, esophagealdysmotility, sclerodactyly and telangiectasiascharacterizes the CREST syndrome variant [2]. The heart is frequently involved in progressive systemic sclerosis and one of the major cardiac injures is representedby focal myocardial fibrosis randomly distributed throughout the myocardium [3]. Signal-averaged electrocardiography (signalaveraged ECG) is used for recording ventricular late potentials, which are the expression of slowed and disorganized conduction through zones of myocardial scarring providing the substrate for reentrant ventricular arrhythmias [4]. Some investigators have hypothesized that myocardial scarring in systemic sclerosis could produce areas of delayed myocardial activation [5]. Echocardiography is a non-invasive technique for the evaluation of the left ventricular function. Previous echocardiographic studies reported an impairment of systolic left ventricular function and an abnormal pattern of left ventricular filling indices in patients with progressive systemic sclerosis [6-81. The aims of the study were: (a) the evaluation by signal-averagedECG and echocardiography of the myocardial involvement in scleroderma patients without clinical and electrocardiographic evidence of cardiac disease,and (b) the assessmentof the signal-averagedECG and echocardiographic findings in two groups of scleroderma patients, i.e. those with the diffuse form of progressivesystemic sclerosisand those with the CREST variant. 2. Materials and methods 2.1. Patients This study was carried out on 15 outpatients (1 male and 14 female, mean age 51 f 9 years, range 35-70) attending the Center for Autoimmune Diseasesof the University ‘La Sapienxa’ of Rome.
The diagnosis of progressivesystemicsclerosiswas made according to the criteria of the American Rheumatism Association [2]. Informed consent was obtained from all subjects enrolled and the study was approved by the local ethics committee. Seven patients (1 male and 6 females, mean age 55 f 3) had diffuse progressive systemicsclerosis; 6 of thesewere positive for antinuclear antibodies of the ‘speckled’ or ‘nucleolar’ patterns (indirect immunofluorescence on Hep-2 cells) and 3 had anti Scl-70 (antitopoisomerase I) antibodies (ANA-Profile, Euroimmun GmbH, Ltibeck, Germany). Eight patients, all female (mean age 49 * 1I), had the CREST syndrome; all of these were positive for anticentromere antibodies. Eighteen normal subjects, 13 male and 5 female aged 33-68 (mean 46 f 13) were studied as controls. None of the subjectsincluded in this study had evidence of cardiac disease as assessedby history, physical examination and standard 12-lead ECG. Patients with echocardiographic evidence of pericardial or valvular involvement were excluded. 2.2. Signal-averagedECG The signal-averagedECG was recorded using a Schiller computerized multi-channel device (model Cardiovit CS 6/12 VME 5.5) with 800 Hz sampling frequency, 12 bit resolution and O-500 Hz frequency response.During the first 10 s of the measurement a sample beat (template) was decided. A signal averaging of the actual heart beat only took place when there was a correlation of more than 98% between the actual heart beat and the template. A number of cardiac cycles (250) was averagedto decreasenoise to a level < 0.2 PV with subjects lying quietly supine. After the signal averaging the ECG data were filtered using a high passwith limit frequenciesof 40 Hz and a low pass filtering at 250 Hz According to Simson’s methods [9], the so-called vector magnitude was calculated after the filtering for the data evaluation. The start of the vector magnitude was equal to the QRS start in the unfiltered leads; the end of the vector magnitude was the endpoint of a 6 ms duration in which the vector magnitude was larger than the sum of the noise plus 2.5 times the standard deviation. Finally, the highly frequent QRS
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duration of thesevector amplitudes, the root mean squarevoltage of the last 40 ms and the part of the vector amplitude below 40 c(V (low amplitude signals) were calculated. Criteria for an abnormal signal-averagedECG included two of the following: (1) QRS duration > 114 ms, (2) root mean square voltage < 20 FV, and (3) low amplitude signals duration > 38 ms [lo-121. 2.3. Echocardiography The study was performed using a HewlettPackard Sonos 100 ultrasound imaging system with a 2.5 MHz transducer. All subjects were studied by M-mode, two-dimensional and Doppler (continuous and pulsed wave) echocardiography. M-mode echocardiography was performed according to the American Society of Echocardiography [ 131,and left ventricular end-diastolic and end-systolic cavity dimension, left atrial cavity dimension, ventricular septal and left ventricular posterior wall thickness were obtained. Ejection fraction was calculated according to the cube formula. Fractional shortening was defined as the difference between the left ventricular diastolic and systolic dimensions divided by the diastolic dimension. Velocity of circumferential fibre shortening was calculated as fractional shortening divided by left ventricular ejection time. An evaluation of segmentalleft ventricular function was performed using two-dimensional long axis and short axis parasternal views and fourchamber apical view. Left ventricular diastolic filling was studied by pulsed Doppler with an apical four-chamber view
with the samplevolume placed at the mitral leaflet tips. The following measurementswere obtained as the average of three beats [14-161: (1) peak of early diastolic flow velocity EVmax;(2) peak of late diastolic flow velocity A,,-; (3) Ey-/Avmax; (4) the velocity time integral of early diastolic flow (E integral); (5) the velocity time integral of late diastolic flow (A integral); (6) E integral/A integral; (7) rate of decreaseof flow velocity in early diastole (EF slope). The isovohtmic relaxation time, the time interval from the aortic valve closure to the onset of the transmitral flow, was calculated by adjusting the Doppler beam across the outflow tract. The pulsed Doppler of the aortic flow was employed to obtain some indexes of left ventricular systolic function. The following measurementswere calculated on the average of three beats [17,18]: (1) peak flow velocity, (2) flow velocity time integral, (3) acceleration time, (4) ejection time. 2.4. Statistical analysis Values are given as mean and standard deviation. The groups were compared using the independent Student’s t-test for continuous data and the x2 test for categorial data. A value of P < 0.05 was considered statistically significant. 3. Resulta 3.1. Signal-averagedECG Signal-averagedECG results are summarized in Table 1. Late potentials in progressive syste&
Table 1 Signal-averagedECG parameters in patients and in control subjects
QRS(W RMS 0 LAS (m) LP
Controls (n = 18)
PSS (n= 15)
dPSS (n = 7)
CREST (n = 8)
95.16 f 6.54 32.32 f 13.99 30.79 zt 6.47 1118
95.27 f 12.55 26.77 f 15.79 35.33 f 10.36 5/15*
103.43f 12.35. 17.47 + 11.472 44.14 f 7.71*** 5/7*++
88.12 a 7.7+ 34.91 l 14.94 27.62 zk 4.27 O/8
dPSS, diffuse progressive systemic sckrosis; LAS, low amplitude signals; LP, late potentials; PSS, progressive systemic sclerosis; QRS, fdtered QRS duration; RIMS, root mean square voltage. +P < 0.05 vs. controls; *+P s 0.01 vs. controls; **+P s 0.001 vs. controls.
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Table 2 Echocardiographic indexes of left ventrictdar systolic function in patients and in control subjects
EF (%) Fs (%)
VCF (circk) PFV (Ao) (cm/s) V-H (A4 (cd AT 640) (W ET (A4 (m.9
Controls (n = 18)
IJSS(n = 15)
76.58 f 5.58 39.0 f 5.12 1.21 * 0.22 99.58 ZIE10.6 19.58 f 2.06 102.08 f 15.73 307.08 f 35.06
78.25 zt 40.25 * 1.13 l 105.50 f 21.58 f
5.17 4.9 0.17 19.29 3.82
dPSS (n = 7) 75.83 f 4.17 37.83 t 3.37
1.10 f 0.17 106.33 * 19.5 21.67 f: 3.5
109.50f 30.22
113.83f 41.69
307.33 f 34.31
305.83 f 36.39
CREST (n = 8) 80.67 f 5.24 42.67 f 5.24
1.17 l 0.19 104.67 f 20.9 21.5 EIE4.46 98.50 f 15.98 308.83 zt 35.50
AT (Ao), aortic acceleration time; dPSS,diffuse progressivesystemicsclerosis;EF, left ventricular ejection fraction; ET (Ao), aortic ejection time; FS, left ventricular fractional shortening; PFV (Ao), peak aortic flow velocity; PSS,progressivesystemicsclerosis;VCF, velocity of cimmnferential fibre shortening; VT1 (Ao), velocity time integral of aortic flow.
sclerosisoccurred in 5 out of 15 patients (33%) vs. 1 out of 18control8 (5.5%). The difference between the two groups was statistically significant (P < 0.05). Analysis of the results in the two subgroups of patients revealed that late potentials were present in 5 of 7 patients with diffuse progressive systemic sclerosis (71.4%), the difference vs. normal controls being statistically significant at the level of P < 0.001. In contrast, none of the patients with CREST syndrome showed late potentials. The mean values of QRS, root mean square voltage and low amplitude signals recorded among the 15 patients with progressive systemic sclerosis
did not statistically differ from those found in normal controls. However, the analysis of the results in the two subgroups of progressive systemic sclerosispatients showed that the subgroup of patients with diffuse progressive systemic sclerosis had highly significant differences as compared with normal controls. QRS, 103.43ms f 12.35vs. 95.16 ms A 6.54 (P = 0.03); root mean square voltage, 17.47PV AE11.47 vs. 32.32 PV f 13.99 (P = 0.02); low amplitude signals: 44.14 ms f 7.71 vs. 30.79 ms i 6.47 (P < 0.001). No signi& cant differenceswere found in the mean values of the signal-averaged ECG parameters in the
Table 3 Echocardiographic indexes of IeR ventricuhu diastolic function in patients and in control subjects
E integral (cm) A integral (cm) E/A integral EF slope (cmkz, IVRT (ms)
Controls (n = 18)
Pss (n = 15)
81.50 47.67 1.72 10.22 3.64 3.20 410.83 69.17
69.93 f 58.40 zt 1.23 f 7.35 zt 4.75 + 1.73 * 352.40 f 86.0 *
+ 11.77 +c 7.56 zt 0.31 f 4.18 l 1.17 f 0.71 f 64.23 a 5.97
19.45 12.31;. 0.37*** 2.31. 1.96 0.755' 73.92+ 14.04***
dPSS (n = 7) 63.0 zt 19.43' 60.0 f 15.19.
1.11 zt 0.42** 6.71 5.17 1.51 317.43 93.57
zk 2.80 f 2.49 +z 0.8*** f 64.1955 ~JZ13.76***
CREST (n = 8) 76.0 i 18.52 57.0 * 10.03* 1.35 f 0.30** 7.79 l 1.77 4.39 f 1.42 1.92 zk 0.58*** 384.75 + 70.84 79.37 f 11.16.
A integral, velocity time integral of late diastolic flow; A ,,-, peak late diastolic flow velocity; dPSS, diffuse progressive systemic sclerosis;E integral, velocity time integral of early diastolic flow; EF slope, rate of decreaseof flow velocity in early diastole; Ev-, peak early diastolic flow velocity; IVRT, isovolumic relaxation time; PSS, progressive systemic sclerosis. *P < 0.05 vs. controls; l *P s 0.01 vs. controls; l **P S 0.001 vs. controls.
hf. Paradiso et al. /International Journal of Cardiology 53 (19%) 171-177
CREST subgroup vs. controls, except for a shorter QRS duration (88.12 ms f 7.7 vs. 95.16 ms * 6.54; P = 0.02). 3.2. Echocardiography
Compared with the control group, progressive systemic sclerosis patients showed no differences in cardiac chamber dimensions and wall thickenings. All progressive systemic sclerosis patients and controls showed a well preservedleft ventricular systolic function (Table 2). Abnormalities of left ventricular filling dynamic were found in 9 progressive systemic sclerosis patients (5 with diffuse progressive systemic sclerosis and 4 with CREST) with a P value < 0,001. Compared with control subjectsthesepatients showed a significant decrease of Ev,,JAvmax (1.23 * 0.3 vs. 1.72 f 0.31; P = 0.001) and E integral/A integral (1.73 AZ0.7 vs. 3.20 A 0.71; P < O.OOl),a lower EF slope (352.40 cm/s* f 73.92 vs. 410.83 cm/s2 * 64.23) and a prolonged isovolumic relaxation time (86.0 ms * 14.04 vs. 69.17 ms f 5.97; P = 0.001). The diffuse progressive systemic sclerosis subgroup showed lower values of E V,,JAVmax,E integral/A integral and EF slope, and higher values of isovohunic relaxation time in comparison with the CREST subgroup (Table 3). 4. Discrmxlon Myocardial involvement in progressive systemic sclerosis is morphologically characterized by a spectrum of focal injuries ranging from contraction band necrosis to replacement fibrosis, and no extramural or intramural vascular abnormalities can be seen to account for the damage [3]. This kind of involvement is frequently found in autopsy studies [3] but is lesseasyto detect clinically. Clinical evidence of myocardial involvement determines a poor prognosis [19,20]. In the past few years several studies with non-invasive techniques have provided strong evidence for a subclinical myocardial involvement in the population with progressive systemic sclerosis [5-8,21-251. The principal clinical application of signalaveragedECG is to provide risk stratification for arrhythmic eventsin the post-infarction period [9].
175
However, the presenceof late potentials has been associatedwith myocardial fibrosis even in the absenceof myocardial infarction [26]. M-mode, twodimensional and Doppler echocardiography represent relatively simple methods for evaluation of the effect of the progressive systemic sclerosis on the left ventricular function [7,8]. The alterations of left ventricular function can be explained by myocardial inflammation, fibrosis or myocardial ischemia due to a Raynaud’s-like phenomenon of the intramyocardial arteries [3]. Compared with controls, a significantly increased prevalence of late potentials and altered left ventricular diastolic filling was found in our progressivesystemic sclerosispatients and, in this respect, our results are consistent with other reported data [5,8,27-301. A previously unrecorded finding emerging from this study is the different pattern of cardiac abnormalities detectable by signal-averagedECG in the two subgroups of progressive systemic sclerosis patients. In fact, signal-averagedECG showed opposite trends in diffuse progressive systemic sclerosisand in CREST. Only patients with diffuse progressivesystemicsclerosisshowed a significant positivity both regarding late potentials presence and as mean values of each parameter. Root mean square voltage and low amplitude signals showed no significantly different values in the CREST patients in comparison with the controls. The different prevalence found in women, who are characterizedby a lower left ventricular mass [31], can explain the shorter QRS duration shown in CREST patients than in controls. Our signalaveraged ECG results showed that myocardial fibrosis can determine the signal fragmentation related to late potentials presenceonly in the diffuse form of progressive systemic sclerosis. In the progressive systemic sclerosispatients we found a significant prevalence of abnormal left ventricular diastolic filling characterized by reduced E,,-lAV,, and E integral/A integral, a lower deceleration rate of early diastolic flow velocity (EF slope) and a prolonged isovolumic relaxation time. None of thesepatients had systemic hypertension, left ventricular hypertrophy, clinical evidenceof coronary artery diseaseor altered left ventricular systolic function.
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In the analysisof eachsinglepatient the signalaveragedECG data and echocardiographicparameterswere found to agreein only a few cases. However,the meanvaluesof diastolic function indexeswere found to be more severelyimpaired in diffuse progressive systemic sclerosis than in CREST (Table 3). This observation is in accordancewith the presenceof the late potentialsonly in the diffuse progressivesystemicsclerosisform (Table 1). only a few studiesrefer to cardiac involvement in scleroderma according to the form of the disease.An increasedprevalenceof ventricular arrhythmias was reported in patients with diffuse progressivesystemicsclerosis[23] and studieswith thallium scanninghaveshown a better left ventricular function in CREST syndromethan in diffuse progressivesystemic sclerosis [22]. In contrast, Kostis et al,, in a study performed with ambulatory electrocardiography,did not find significant differencesin the prevalenceof arrhythmiasin the
Table 4 Late potentials and left ventricular diastolic dysfunction in the two clinical expressionsof progressive systemic sclerosis
caseno. dPSS 1 2 3 4 5 6 7 CREST 1 2 3 4
LP
DD
+
+
+ + + +
+ + + + +
+ +
5 6 7
+
8 dpsS, dithse progressive systemic sclerosis; DD, diastolic dysfunction; LP, late potentials; PSS, progressive systemic sclerosis.
two main clinical forms of progressivesystemic sclerosis[24]. In our patients,who had beenselectedfor having no clinical evidenceof cardiacinvolvementand electrocardiographicabnormalities,the combined utilization of echocardiographyand signal-averaged ECG permitted a more completeevaluation of myocardialinvolvement.In all the patientswith the diffuseform of the diseaseat leastone method was found to givealtered results.The presenceof abnormalfindingswith both the methodscould be an indication of a more advancedmyocardial fibrosis.On the other hand, half of the patientswith CREST syndromedid not show any pathological findings with either technique(Table 4). Theseresults are consistentwith a less severemyocardial involvementin CREST syndromeas well as with the reported clinical finding 1221of a significantly longer duration of diseasein thesepatients compared with the diffuse progressivesystemicsclerosisgroup. The absenceof both echocardiography and signal-averagedECG alterationsprobably accounts for a better prognosis. The results obtained with the two methods could be related to a different expressionof myocardial involvement.Further follow-up studiesare neededfor a better definition of the clinical implications of the signal-averagedECG and echocardiographicdata. References [I] Medsger TA. Progressivesystemicsclerosis.Clin Rheum Dis 1983;9: 655-670. [21 Subcommitteefor Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic criteria committee. Prelimimuy criteria for the classiication of systeh sclerosis (schoderma). Arthritis Rheum 1980,23z 581-590. 131 Bulkley BH. Ridol!i RL, Salyer WR, Hutchins GM. Myocardhl lesions of progressive systemic sclerosis. A cause of cardiac dysfunction. Circulation 1976; 53: 483-490. 141 Simson MB, Untereker WJ, Spielman SR et al. Relation between late potentials on the body surface and directly recorded fragmented electrocardiograms in patients with ventricular tachycardia. Am J Cardioll983; 51: 105-l 12. 151 Moser DK, StevensonWG. Woo MA et al. Frequency of late potentials in systemic sclerosis.Am J Cardiol 1991; 67: 541-543. [61 Gottdiener JS, Moutsopoulos HM, Decker JL. Echocar-
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